Pyrazole and imidazole derivatives, compositions and methods as orexin antagonists

ABSTRACT

The present invention is directed to substituted Pyrazole and Imidazole derivatives of compounds that are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or implicated. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/856,822 filed on Jun. 4, 2019, the contents are which are herebyincorporated into this application in its entirety.

FIELD OF THE DISCLOSURE

This disclosure pertains to compounds, compositions and methods forusing orexin antagonists to treat or ameliorate human and animaldiseases as therapeutic agents. In particular, any pathological disorderin which both types of orexin receptors are pharmacologically involvedor implicated. These important therapeutic applications include but arenot limited to treating central nervous system (CNS) disorders andneurological diseases that involve or are modulated by orexin receptorsincluding but not limited to disorders that are responsive to orexinreceptor antagonists, e.g., substance addiction and dependence,cognitive impairment, Alzheimer's disease (AD), posttraumatic stressdisorder (PTSD), schizophrenia, panic, anxiety, autism, and depression.

BACKGROUND INFORMATION

The orexins (also known as hypocretins) are comprised of two excitatoryhypothalamic neuropeptides: orexin A (OX-A; a 33 amino acid peptide) andorexin B (OX-B; a 28 amino acid peptide). They were simultaneouslydiscovered in 1998 by two research groups searching for new signalingmolecules, (1) Sakurai and co-workers (who named them orexin-A and -B)(Sakurai, T. et al, Cell 1998, 92, 573) and (2) de Lecea and co-workers(who named them hypocretin 1 and 2, respectively) (de Lecea, L. et al,Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 322). These neuropeptides areendogenous ligands for two G protein-coupled receptors (GPCR) named OX₁Rand OX₂R (also referred to as Hcrt1 and Hcrt2, respectively) and arederived proteolytically from the same precursor peptide calledpre-pro-orexin polypeptide (Sakurai T., et al. The Journal of biologicalchemistry. 1999; 274, 17771-17776). Though structurally related, thebinding affinities of these endogenous ligands for the two GPCRs differ.Orexin A binds to OX₁R with about 100-fold higher affinity than OrexinB, whilst both Orexin A and Orexin B bind to OX2R with the same affinity(Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). Soon after thediscovery of orexins, modulation of the orexin signaling was originallyconsidered for potential novel treatments of narcoleptic or insomniacpatients since the role of orexins in regulation of sleep andwakefulness was well-studied and understood, and the discovery ofsmall-molecule modulators of orexin signaling facilitated thedevelopment of this class of compounds. Narcoleptic patients show adiminished activity in hypothalamic orexin neurons thereby lowering theamounts of circulating orexins in the cerebrospinal fluid. In contrast,activation of orexin neurons maintains wakefulness and arousal. Theeffects of orexin signaling on feeding and energy homeostasis were alsoestablished earlier and found to be coordinated to the sleep-wake cycle(Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). More recentstudies have established the role of orexin signaling in other keyphysiological pathways such as neuroendocrine functions (Inutsuka, A.;Yamanaka, A. Front. Endocrinol. 2013, 4:18. doi:10.3389/fendo.2013.00018), glucose metabolism (Tsuneki, H., et al.,Endocrinology, 2016, 157, 4146-4157), stress-adaptive responses (Xiao,F., et al. Neuropharmacology, 2013, 67, 16-24), andaddiction/reward-seeking (Aston-Jones, G., et al. Brain Res., 2010,1314, 74-90). Small molecule orexin antagonists have been broadlycategorized into three classes based on their overall receptorselectivity profiles: (1) DORA (dual-acting, or non-selective OX₁R/OX₂Rantagonists), (2) SORA-1 (selective OX₁R antagonists), and (3) SORA-2(selective OX₂R antagonists). It has been shown that while OX₂R knockoutmice and OX₁R/OX₂R double knockout mice both show a narcolepticphenotype, the effect is very muted in OX₁R knockouts (Wang C., et al.Neurosci., 2018, 11, 220. doi: 10.3389/fnmol.2018.00220). Additionally,both DORA and SORA-2 compounds inhibit wakefulness, but SORA-1 compoundsdo not—thus suggesting that narcoleptic effects are mediated throughOX₂R or a combination of OX₁R and OX₂R, but not through OX₁R alone.Thus, it is clear that the discovery and development of selective orexinantagonists is crucial to the advancement of this field but mostimportantly to the development of therapeutic agents for dysregulatedbiological processes that involve the orexin receptor; especially fornon-sleep related indications such as substance addiction.

SUMMARY OF THE DISCLOSURE

This disclosure addresses the aforementioned therapeutic and/or otherneeds and problems in the art by providing compounds of formula I:

wherein the variables are as defined herein, including anypharmaceutically acceptable salts, solvates, adducts, polymorphs, andisomers thereof, as well as compositions comprising the same. In someembodiments, compounds of formula I and compositions comprising the samecan be used to treat conditions such as those described herein, such asthrough activity as Orexin receptor antagonists. Thus, the compoundsand/or compositions of the same can be referred to herein as “Orexinreceptor antagonists”.

In some embodiments, this disclosure also provides compositions thatcomprise the above compounds and/or a pharmaceutically acceptable saltthereof. In some aspects, this disclosure provides methods for treatingCNS disorders such as, among others, substance addiction and dependence,posttraumatic stress disorder (PTSD), schizophrenia, panic, anxiety anddepression, cognitive impairment and Alzheimer's disease (AD) in asubject in need or at risk thereof, the methods comprising the step ofadministering to said subject a therapeutically effective amount ofOrexin receptor antagonists or a pharmaceutically acceptable saltthereof. In certain embodiments, the Orexin receptor antagonists or apharmaceutically acceptable salt thereof could be formulated to beadministered periodically, for example and without limitation, every 3,6 to 24 hours as deemed clinically beneficial. Other aspects andembodiments are contemplated herein as would be understood by those ofordinary skill in the art.

DETAILED DESCRIPTION

This disclosure pertains to a fused six (6) and five (5) membered ringsystem derivatives of formula (I) wherein the fused 6 & 5 membered ringsare as described herein with enabling structural descriptions, topharmaceutically acceptable salts thereof, to the preparation of thesame, to pharmaceutical compositions containing one or more compounds offormula (I), and to the use of the same as pharmaceuticals and/ortherapeutic agents, particularly (i.e., in preferred embodiments) to theuse of the same as orexin receptor antagonists (“Orexin receptorantagonists”). These novel agents as described by formula (I) which arenon-peptide antagonists of human orexin receptors and are potentiallyuseful in the treatment of disorders relating to orexinergicdysfunctions; including but not limited for such disorders likesubstance addiction, anxiety, panic, cognitive dysfunctions, mood, orappetite, sleep, Alzheimer (AD), metabolic syndrome, and hypertension;and especially these compounds could be of great therapeutic value inthe treatment of anxiety disorders, addiction disorders, and sleepdisorders.

In some embodiments, this disclosure provides compounds of formula (I):

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring); when R₁is heteroaryl, it is preferred as a 5 or 6-membered heteroaryl selectedfrom the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl,thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl,and pyridazinyl; wherein said aromatic, aryl or heteroaryl isunsubstituted, mono-, or di-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy and (C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂and/or R₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,3)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl or substituted alkyl; and R₅ and R₆ can be connected asalkyl to form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; and R₅ and R₆can be connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, or nothing (to provide five membered pyrrolidine ring);wherein the carbon atom at position 2 of the of the piperidine orpyrrolidine is preferred in absolute (S)-configuration; in contrast, thecarbon atom at position 2 of the of the morpholine ring (when X=O,oxygen) is preferred in absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, or(C₂₋₇)cycloalkyl;wherein:the fused ring system A-B-J-D-E is a five (5)-membered heteroaryl;the fused ring system B-J-M-G-K-L is a six (6)-membered aromatic oraryl, heteroaryl, cycloalkyl, heterocycloalkyl;wherein, preferably:A=Nitrogen (N); and/or,B=Carbon (C) or Nitrogen (N); and/or,J=Carbon (C) or Nitrogen (N); and/or,D=Carbon (C); and/or,E=Carbon (C); and/or,M=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,G=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,K=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,L=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O;or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof.

In some preferred embodiments, this disclosure provides a compounds offormula II, wherein the ring system (illustrated by A-B-J-D-E variablesin formula (I) fused to the six (6)-membered ring is preferably animidazolo ring system as represented by formula (II):

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl; R₂ and R₃ independently=H, halogen (such as F, Cl, Bror I), alky group, substituted alkyl, (C₁₋₄ alkyl, (C₁₋₄)alkoxy,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and (C₃₋₇)cycloalkyl; wherein eachof R₂ and R₃ is independently and optionally substituted at eachsubstitutable position with up to 3 substituents independently selectedfrom one or both R₂ & R₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄ alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, nothing (to provide five membered pyrrolidine ring); whereinthe carbon atom at position 2 of the of the piperidine or pyrrolidine ispreferred in absolute (S)-configuration; in contrast, the carbon atom atposition 2 of the of the morpholine ring (when X=O, oxygen) is preferredin absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂,NR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₂₋₇)cycloalkyl;wherein preferably:M=Carbon, CH, CR₂R₃, CR₂, CR₃, or O; and/or,G=Carbon, CH, CR₂R₃, CR₂, CR₃, or O; and/or,K=Carbon, CH, CR₂R₃, CR₂, CR₃, or O; and/or,L=Carbon, CH, CR₂R₃, CR₂, CR₃, or O.

In some preferred embodiments of this disclosure provides compounds offormula III, wherein the ring system (illustrated by A-B-J-D-E variablesin formula (I) fused to the six (6)-membered ring is a pyrazolo ringsystem as represented by formula (III):

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and (C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy,(C₃₋₇)cycloalkyl, or (C₁₋₃)heterocycloalkyl;R₅=CH₃, alkyl, or substituted alkyl, where R₅ and R₆ can be connected asalkyl to form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃) alkyl bridge cyclic structure;X=CH₂, O, or nothing (to provide five membered pyrrolidine ring);wherein the carbon atom at position 2 of the of the piperidine orpyrrolidine is preferred in absolute (S)-configuration; in contrast, thecarbon atom at position 2 of the of the morpholine ring (when X=O,oxygen) is preferred in absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl;wherein preferably:M=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,G=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,K=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O; and/or,L=Carbon (C), CH, CR₂R₃, CR₂, CR₃, or O.

In some preferred embodiments, this disclosure provides compoundswherein the imidazole fused six-membered ring is as shown in formulaII-a:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy,(C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, substituted alkyl, R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, substituted alkyl, or R₅ and R₆connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, nothing (to provide five membered pyrrolidine ring); whereinthe carbon atom at position 2 of the of the piperidine or pyrrolidine ispreferred in absolute (S)-configuration; in contrast, the carbon atom atposition 2 of the of the morpholine ring (when X=O, oxygen) is preferredin absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂,NR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl.

In some preferred embodiments, this disclosure provides compoundswherein the imidazole fused six-membered ring is as shown in formulaII-b:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄ alkyl, (C₁₋₄alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ &R₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy,(C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, substituted alkyl, optionally wherein R₅ and R₆ connectedas alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, substituted alkyl, or R₅ and R₆connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, nothing (to provide five membered pyrrolidine ring); whereinthe carbon atom at position 2 of the of the piperidine or pyrrolidine ispreferred in absolute (S)-configuration; in contrast, the carbon atom atposition 2 of the of the morpholine ring (when X=O, oxygen) is preferredin absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl);Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl;

In some preferred embodiments, this disclosure provides compoundswherein the imidazole fused six-membered ring is as shown in formulaII-c:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ &R₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, substituted alkyl; R₅ and R₆ can be connected as alkyl toform a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, nothing (to provide five membered pyrrolidine ring); whereinthe carbon atom at position 2 of the of the piperidine or pyrrolidine ispreferred in absolute (S)-configuration; in contrast, the carbon atom atposition 2 of the of the morpholine ring (when X=O, oxygen) is preferredin absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl.

In some preferred embodiments, this disclosure provides compoundswherein the pyrazole fused six-membered ring is preferred as shown informula III-a:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy,halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, nothing (to provide five membered pyrrolidine ring); whereinthe carbon atom at position 2 of the of the piperidine or pyrrolidine ispreferred in absolute (S)-configuration; in contrast, the carbon atom atposition 2 of the of the morpholine ring (when X=O, oxygen) is preferredin absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl.

In some preferred embodiments, this disclosure provides compoundswherein the pyrazole fused six-membered ring is preferred as shownherein according to embodiment formula III-b:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄ alkyl, (C₁₋₄alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, or nothing (to provide five membered pyrrolidine ring);wherein the carbon atom at position 2 of the of the piperidine orpyrrolidine is preferred in absolute (S)-configuration; in contrast, thecarbon atom at position 2 of the of the morpholine ring (when X=O,oxygen) is preferred in absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); andZ₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl.

In some preferred embodiments, this disclosure provides compoundswherein the pyrazole fused six-membered ring is preferred as shownherein according to embodiment formula III-c:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br or I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy,(C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, or nothing (to provide five membered pyrrolidine ring);wherein the carbon atom at position 2 of the of the piperidine orpyrrolidine is preferred in absolute (S)-configuration; in contrast, thecarbon atom at position 2 of the of the morpholine ring (when X=O,oxygen) is preferred in absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, or (C₂₋₇)cycloalkyl.

In some preferred embodiments, this disclosure provides compoundswherein the pyrazole fused six-membered ring is preferred as shownherein according to embodiment formula III-d:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring);heteroaryl is preferred as a 5- or 6-membered heteroaryl selected fromthe group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl,thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl,and pyridazinyl; wherein said aromatic, aryl or heteroaryl isunsubstituted, mono-, or di-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy and (C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; or R₅ and R₆can be connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;X=CH₂, O, or nothing (to provide five membered pyrrolidine ring);wherein the carbon atom at position 2 of the of the piperidine orpyrrolidine is preferred in absolute (S)-configuration; in contrast, thecarbon atom at position 2 of the of the morpholine ring (when X=O,oxygen) is preferred in absolute (R)-configuration;Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group), CH₂OR₄, CH₂, orNR₄R₇ (where R₇=H, alkyl); and,Z₁ and Z₂ independently=H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy, (C₂₋₇)cycloalkyl;

In some preferred embodiments, this disclosure provides compoundswherein the stereogenic centers and main scaffold rings are preferred asshown in the exemplification formula as shown herein according toembodiment formula II-aa-ac, II-ba-bc, and II-ca-cc:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, or substituted heteroaryl (5-6 membered ring);heteroaryl is preferred as a 5- or 6-membered heteroaryl selected fromthe group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl,thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl,and pyridazinyl; wherein said aromatic, aryl or heteroaryl isunsubstituted, mono-, or di-substituted, wherein the substituents areindependently selected from the group consisting (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy and (C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br, I), alky group,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen (such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, (C₃₋₇)heterocycloalkyl;R₅=CH₃, alkyl, or substituted alkyl; R₅ and R₆ can be connected as alkylto form a (C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;and,Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group (CH₂ in formulasII-aa-ac, II-ba-bc, and II-ca-cc)), CH₂OR₄, CH₂, or NR₄R₇ (where R₇=H,alkyl).

In some preferred embodiments, this disclosure provides compoundswherein the stereogenic centers and main scaffold rings are preferred asshown in the exemplification formula as shown herein according toembodiment formula III-aa-ac, III-ba-bc, and III-ca-cc:

wherein:R₁=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroarylis preferred as a 5- or 6-membered heteroaryl selected from the groupconsisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, andpyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from the group consisting of (C₁₋₄ alkyl, (C₁₋₄)alkoxy, halogen(such as F, Cl, Br or I), (C₁₋₃)fluoroalkyl, (C₁_ 3)fluoroalkoxy and(C₃₋₇)cycloalkyl;R₂ and R₃ independently=H, halogen (such as F, Cl, Br, I), alky group,substituted alkyl, (C₁₋₄alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy or (C₃₋₇)cycloalkyl; wherein each of R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to 3 substituents independently selected from one or both R₂ andR₃;R₄=aromatic or aryl, heteroaryl (5-6 membered ring), substitutedaromatic or aryl, substituted heteroaryl (5-6 membered ring); whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-, ordi-substituted or tri-substituted, wherein the substituents areindependently selected from the group consisting of (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy,(C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl; R₅=CH₃, alkyl, orsubstituted alkyl; R₅ and R₆ can be connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure;R₆=H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R₅ and R₆ canbe connected as alkyl to form a (C₁₋₃)alkyl bridge cyclic structure;and,Y=NH, O, nothing (to attach R₄ directly to CZ₁Z₂ group (CH₂ in formulasIII-aa-ac, III-ba-bc, and III-ca-cc)), CH₂OR₄, CH₂, NR₄R₇ (where R₇=H,alkyl).

In more preferred embodiments, this disclosure provides compounds offormula I, II, III, II-a, II-b, II-c, III-a, III-b and III-c shownbelow:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof.

The term “alkyl” as used herein means a linear or branched carbon chain(e.g., having the general formula C_((n))H_((2n+1))) including but notlimited to any of C₁-C₁₀₀ (e.g., methyl, ethyl, propyl, and the like).The term “fluroalkyl” as used herein means an alkyl substituted by atleast one flourine atom. The term “alkoxy” as used herein means an alkylbonded to oxygen (i.e., R—O). The term “fluoroalkoxy” as used hereinmeans an alkoxy substituted by at least one fluorine atom. The term“heterocycloalkyl” as used herein means a cycloalkyl comprising at leastone heteroatom (e.g., N and/or O) within the cyclic ring thereof. Theterm “aryl” as used herein means a monocyclic or bicyclic carbocyclicaromatic or aryl ring system. Phenyl is an example of a monocyclicaromatic or aryl ring system. The term “heteroaryl” as used herein meansa monocyclic or bicyclic aromatic or aryl ring system having 1 to 3heteroatom or heteroatom groups in each ring selected from O, N, NH or Sin a chemically stable arrangement. In such a bicyclic aromatic or arylring system embodiment of “heteroaryl”: both rings may be aromatic oraryl; and one or both rings may contain said heteroatom or heteroatomgroups. Examples of heteroaryl rings include 2-furanyl, 3-furanyl,N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl(e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl(e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl),2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g.,2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl,1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl(e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The terms“cycloalkyl” or “cycloalkenyl” refers to a monocyclic or fused or(C₁₋₃)alkyl bridged bicyclic carbocyclic ring system that is notaromatic or aryl. Cycloalkenyl rings have one or more units ofunsaturation. Preferred cycloalkylor cycloalkenyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, norbornyl, adamantly and decalinyl. While“halogen” can be F, Cl, Br or I, preferred embodiments are those inwhich halogen is F, CI or Br. The term “substituted” as used hereinmeans, for a particular group (e.g., alkyl, aryl, heteroaryl, aromatic),the replacement of one functional group by another (e.g., thesubstitution of an alkyl hydrogen by fluorine to provide fluoroalkyl).

Any embodiment given herein is also intended to represent unlabeledforms as well as isotopically labeled forms of the compounds, unlessotherwise indicated. Isotopically labeled compounds have structuresdepicted by the formulas given herein except that one or more atoms arereplaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of thisdisclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁶Cl, ¹²⁵I, respectively. The disclosure includes variousisotopically labeled compounds as defined herein, for example those intowhich radioactive isotopes, such as ³H, ¹³C, and ¹⁴C, are present. Suchisotopically labelled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques, such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or labeledcompound may be particularly preferred for PET or SPECT studies.Isotopically labeled compounds of this disclosure and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Many of the compounds useful in the methods and compositions of thisdisclosure have at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem. (1976), 45, 11-30. The disclosure also relates to allstereoisomeric forms such as enantiomeric and diastereoisomeric forms ofthe compounds or mixtures thereof (including all possible mixtures ofstereoisomers). See, e.g., WO 01/062726 (see also US 2017/0022208 A1, US2017/0253603 A2). Furthermore, multiple substituents on a piperidinyl orpyrrolidinyl ring can also be in either cis or trans relationship toeach other with respect to the plane of the piperidinyl or thepyrrolidinyl ring. Such forms or geometric isomers, although notexplicitly indicated in the formulae described herein, are intended tobe included within the scope of the present disclosure. With respect tothe methods and compositions of the present disclosure, reference to acompound or compounds is intended to encompass that compound in each ofits possible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Pharmaceutically acceptable salts is used herein to refer to an agent ora compound according to the invention that is a therapeutically active,non-toxic base and acid salt form of the compounds. The acid additionsalt form of a compound that occurs in its free form as a base can beobtained by treating said free base form with an appropriate acid suchas an inorganic acid, for example, a hydrohalic such as hydrochloric orhydrobromic, sulfuric, nitric, phosphoric and the like; or an organicacid, such as, for example, acetic, hydroxyacetic, propanoic, lactic,pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclic, salicylic, p-aminosalicylic, pamoic and the like. See, e.g., WO01/062726 (see also US 2017/0022208 A1, US 2017/0253603 A2).

Compounds containing acidic protons may be converted into theirtherapeutically active, non-toxic base addition salt form, e. g., metalor amine salts, by treatment with appropriate organic and inorganicbases. Appropriate base salt forms include, for example, ammonium salts,alkali and alkaline earth metal salts, e. g., lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, and salts with amino acids such as, for example, arginine, lysineand the like. Conversely, said salt forms can be converted into the freeforms by treatment with an appropriate base or acid. Compounds and theirsalts can be in the form of a solvate, which is included within thescope of the present disclosure. Such solvates include for examplehydrates, alcoholates and the like.

The compounds of the present invention also include prodrugs, analogs orderivatives. The term “prodrug” is a recognized art in the field and isintended to encompass compounds or agents which, under physiologicalconditions, are converted into orexin antagonists. A common method formaking a prodrug is to select moieties which are hydrolyzed ormetabolized under physiological conditions to provide the desiredcompound or agent. In other embodiments, the prodrug is converted by anenzymatic activity of the host animal to an orexin antagonist.

This disclosure also includes isotopically labelled, especially ²H(deuterium) labelled compounds of all formulas, which compounds areidentical to the compounds of all formulas described herein except thatone or more atoms have each been replaced by an atom having the sameatomic number but an atomic mass different from the atomic mass usuallyfound in nature. Isotopically labelled, especially ²H (deuterium)labelled compounds of all formulas and salts thereof are within thescope of this disclosure. Substitution of hydrogen with the heavierisotope ²H (deuterium) may lead to greater metabolic stability resultinge.g., in increased in-vivo half-life or reduced dosage requirements, ormay lead to reduced inhibition of cytochrome P450 enzymes, resultinge.g., in an improved safety profile. In another aspects of embodiment ofthe invention, the compounds of all formulas are not isotopicallylabelled. However, isotopically labelled compounds of all formula couldbe prepared by anyone skilled in the art in analogy to the methodsdescribed hereinafter but using the appropriate isotopic variation ofsuitable reagents or starting materials.

In some embodiments, this disclosure provides methods for preparing thecompounds disclosed herein. In preferred embodiments, the compounds ofthis disclosure are prepared using the methods described in the Examplesbelow, or suitable variants thereof as would be understood by those ofordinary skill in the art. In some embodiments, the methods can comprisethe use of intermediate compounds such as those disclosed herein, withspecific uses of such intermediates being described in more detail inthe Examples section. Thus, in some embodiments, this disclosureprovides intermediates (e.g., Intermediates A through J shown in theExamples section below) that can be used to produce the compounds of theformulas disclosed herein, such as but not limited to Examples 1 through21. In some embodiments, this disclosure also provides intermediatesused to produce intermediates A through J. In preferred embodiments,such intermediates can include Intermediate A, Intermediate A1,Intermediate A2, Intermediate A3, and/or Intermediate A4; Intermediate Band/or Intermediate B1; Intermediate C and/or Intermediate C₁;Intermediate D and/or Intermediate D1; Intermediate E and/orIntermediate E1; Intermediate F, Intermediate F1 and/or Intermediate F2;Intermediate G and/or Intermediate G1; Intermediate H and/orIntermediate H1; Intermediate I, Intermediate I1, and/or IntermediateI2; Intermediate J and/or Intermediate J1. In some embodiments,Intermediate A and Intermediate F can be used to produce a compound ofExample 1. In some embodiments, Intermediate A and Intermediate B can beused to produce a compound of Example 2. In some embodiments,Intermediate A and Intermediate C can be used to produce a compound ofExample 3. In some embodiments, Intermediate J and Intermediate D can beused to produce a compound of Example 4. In some embodiments,Intermediate A and Intermediate D can be used to produce a compound ofExample 5. In some embodiments, Intermediate J and Intermediate E can beused to produce a compound of Example 6. In some embodiments,Intermediate A and Intermediate E can be used to produce a compound ofExample 7. In some embodiments, Intermediate I and Intermediate E can beused to produce a compound of Example 8. In some embodiments,Intermediate I and Intermediate D can be used to produce a compound ofExample 9. In some embodiments, Intermediate J and Intermediate B can beused to produce a compound of Example 10. In some embodiments,Intermediate I and Intermediate B can be used to produce a compound ofExample 11. In some embodiments, Intermediate I and Intermediate F canbe used to produce a compound of Example 12. In some embodiments,Intermediate J and Intermediate F can be used to produce a compound ofExample 13. In some embodiments, Intermediate I and Intermediate C canbe used to produce a compound of Example 14. In some embodiments,Intermediate J and Intermediate C can be used to produce a compound ofExample 15. In some embodiments, Intermediate A and Intermediate G canbe used to produce a compound of Example 16. In some embodiments,Intermediate A and Intermediate H can be used to produce a compound ofExample 17. In some embodiments, Intermediate I and Intermediate H canbe used to produce a compound of Example 18. In some embodiments,Intermediate I and Intermediate G can be used to produce a compound ofExample 19. In some embodiments, Intermediate J and Intermediate H canbe used to produce a compound of Example 20. In some embodiments,Intermediate J and Intermediate G can be used to produce a compound ofExample 21. As used herein, the phrase “can be used” is equivalent to“can be reacted with” (e.g., as shown in the Examples section below).While such methods for preparing the compounds of Examples 1-21 can beused, those of ordinary skill in the art would understand other methodscan also be used.

The compounds of this disclosure can be used for various in vivo methodsof treatment, the compounds can also be used in vitro to inhibit Orexinreceptors type 1 and/or 2 (i.e., Orexin receptors type 1 and/or 2antagonists). For instance, in some embodiments, Chinese hamster ovary(CHO) cells expressing the human orexin-1 receptor and/or the humanorexin-2 receptors can be incubated with one or more antagonists orpotential antagonists (e.g., compounds of Examples 1-21) and one or moreindicator compounds (e.g., fluorescent calcium indicator such as fluo-4AM) along with one or more agonists, and antagonist activity measuredusing a Fluorescent Imaging Plate Reader (FLIPR Tetra, MolecularDevices). Antagonistic activity can be recorded as the 50% inhibitoryconcentration (IC₅₀) values. Other suitable methods for identifyingantagonistic compounds are also known to those of ordinary skill in theart.

Thus, in some embodiments, his disclosure provides compounds that can beused for in vivo treatments of various disease states, and/or in vitro(e.g., as Orexin receptors type 1 and/or 2 antagonists). In someembodiments, this disclosure provides compounds of formulas I, II, III,IIa, IIb, IIc, IIIa, IIIb, IIIc, IIaa, IIab, IIac, IIba, IIbb, IIbc,IIca, IIcb, IIcc, IIIaa, IIIab, IIIac, IIIba, IIIbb, IIIbc, IIIca,IIIcb, and/or IIIcc, or as may be otherwise disclosed and/orcontemplated herein:

-   or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,    isomer, or combination thereof; wherein:-   R₁ is selected from the group consisting of aromatic, aryl, five or    six member heteroaryl, substituted aromatic, substituted aryl,    substituted five or six member heteroaryl; optionally wherein said    heteroaryl is selected from the group consisting of pyrrolyl,    pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl,    pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said    aromatic, aryl or heteroaryl is unsubstituted, mono-substituted by    one R₁ substituent or di-substituted by two R₁ substituents, wherein    each R₁ substituent is independently selected from the group    consisting of (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,    (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen is    optionally selected from the group consisting of F, Cl, Br, and I;-   R₂ and R₃ are independently selected from the group consisting of H,    halogen, alkyl, substituted alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,    (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ is    independently and optionally substituted at each substitutable    position with up to three R₂-R₃ substituents, wherein each R₂-R₃    substituent is independently selected from the group consisting of    H, halogen, alkyl, substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy,    halogen, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and    (C₃₋₇)cycloalkyl; wherein the halogen is optionally selected from    the group consisting of F, Cl, Br, and I;-   R₄ is selected from the group consisting of aromatic, aryl, five or    six member heteroaryl; substituted aromatic, substituted aryl, and    substituted five or six member heteroaryl; wherein said aromatic,    aryl or heteroaryl is unsubstituted, mono-substituted by one R₄    substituent, di-substituted by two R₄ substituents, or    tri-substituted by three R₄ substituents, wherein each R₄    substituent is independently selected from the group consisting of    (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen, (C₁₋₃)fluoroalkyl,    (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and (C₃₋₇)heterocycloalkyl;    and wherein the halogen is optionally selected from the group    consisting of F, Cl, Br, and I;-   R₅ is selected from the group consisting of CH₃, alkyl, and    substituted alkyl;-   R₆ is selected from the group consisting of H, halogen, alkyl, and    substituted alkyl, wherein said halogen is selected from the group    consisting of F, Cl, Br, and I;

optionally wherein R₅ and R₆ connected as alkyl to form a (C₁₋₃)alkylbridge cyclic structure;

-   X is absent to provide a pyrrolidine ring, CH₂ to provide a    piperidine ring, or O to provide a morpholine ring; wherein the    carbon atom at position 2 of the of the piperidine ring or the    pyrrolidine ring is optionally in absolute (S)-configuration; and    wherein the carbon atom at position 2 of the of the morpholine ring    is optionally in absolute (R)-configuration;-   Y is absent or selected from the group consisting of NH, O, CH₂OR₄,    CH₂, and NR₄R₇ wherein R₇ is H or alkyl; and,-   Z₁ and Z₂ are each independently selected from the group consisting    of H, F, (C₁₋₄)alkyl, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and    (C₂₋₇)cycloalkyl;

and wherein:

A-B-J-D-E is a five-member heteroaryl;

-   B-J-M-G-K-L is a six-member ring selected from the group consisting    of aromatic, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

and wherein, optionally:

A is N; and/or,

B is C or N; and/or,

J is C or N; and/or,

D is C; and/or,

E is C; and/or,

M is selected from the group consisting of C, CH, CR₂R₃, CR₂, CR₃, O;and/or,

G is selected from the group consisting of C, CH, CR₂R₃, CR₂, CR₃, andO; and/or,

K is selected from the group consisting of C, CH, CR₂R₃, CR₂, CR₃, andO; and/or,

L is selected from the group consisting of C, CH, CR₂R₃, CR₂, CR₃, andO.

In some embodiments, this disclosure provides the preferred compoundsshown below:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof.

In some embodiments, this disclosure provides a composition comprisingany one or more of such a compound, and/or pharmaceutically acceptablesalt, hydrate, solvate, polymorph, isomer, or combination thereof. Insome embodiments, this disclosure provides a pharmaceutical compositioncomprising a compound, pharmaceutically acceptable salt, hydrate,solvate, polymorph, isomer, or combination thereof; and at least onepharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. Insome embodiments, this disclosure provides a therapeutically effectiveamount of such a compound, or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, isomer, or combination thereof. In someembodiments, this disclosure provides such a pharmaceutical compositionfurther comprises at least one second therapeutic agent. In someembodiments, this disclosure provides methods of preventing or treatinga condition selected from the group consisting of a central nervoussystem (CNS) disorder, substance addiction, dependence, panic, anxiety,depression, posttraumatic stress disorder (PTSD), neurodegeneration,autism, schizophrenia, and Alzheimer disease (AD) in a subject in needthereof, by administering to the subject any of such one or morecompounds and/or composition comprising one or more of such compounds,or pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof. In some embodiments, the methods caninclude administering a composition comprising a therapeuticallyeffective amount of the compound, pharmaceutically acceptable salt,hydrate, solvate, polymorph, isomer, or combination thereof. In someembodiments, the composition comprises a pharmaceutically acceptablesalt or isotope of such a compound. In some embodiments, the compositioncan comprise an unlabeled form of the compound or an isotopicallylabeled form of the compound in which the compound has a structuredepicted by the formula wherein one or more atoms are replaced by anatom having a selected atomic mass or mass number. In some embodiments,this disclosure provides for the use of a compound, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, isomer, or combinationthereof, disclosed herein in the preparation of a medicament forpreventing and/or treating a condition selected from the groupconsisting of a central nervous system (CNS) disorder, substanceaddiction, dependence, panic, anxiety, depression, posttraumatic stressdisorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimerdisease (AD) in a subject in need thereof. In some embodiments, the usecan include a composition comprises a therapeutically effective amountof the compound, pharmaceutically acceptable salt, hydrate, solvate,polymorph, isomer, or combination thereof. In some embodiments, such usecan comprise a composition a pharmaceutically acceptable salt or isotopeof the compound. In some embodiments, such use can comprise acomposition comprises an unlabeled form of the compound or anisotopically labeled form of the compound in which the compound has astructure depicted by the formula wherein one or more atoms are replacedby an atom having a selected atomic mass or mass number. This disclosurealso provides intermediates of the compounds disclosed herein as well asmethods for preparing the same. In some embodiments, such methods forpreparing can include using any of the intermediates disclosed herein(e.g., any one or more of Intermediates A-J). Other embodiments are alsocontemplated here as would be understood by those of ordinary skill inthe art.

The disclosure also provides pharmaceutical compositions comprising oneor more compounds of this disclosure (or the like, such as apharmaceutically acceptable salt thereof) (i.e., as an active agent, asa therapeutic agent), and one or more pharmaceutically acceptablecarriers or excipients. A pharmaceutical composition contains atherapeutically effective amount of one ore more of such compounds orthe like (i.e., active agent(s)), or an appropriate fraction thereof. Acomposition can optionally contain an additional active agent. In someembodiments, a peptide product is at least about 90%, 95% or 98% pure.Pharmaceutically acceptable excipients and carriers includepharmaceutically acceptable substances, materials and vehicles.Non-limiting examples of types of excipients include liquid and solidfillers, diluents, binders, lubricants, glidants, surfactants,dispersing agents, disintegration agents, emulsifying agents, wettingagents, suspending agents, thickeners, solvents, isotonic agents,buffers, pH adjusters, absorption-delaying agents, stabilizers,antioxidants, preservatives, antimicrobial agents, antibacterial agents,antifungal agents, chelating agents, adjuvants, sweetening agents,flavoring agents, coloring agents, encapsulating materials and coatingmaterials. The use of such excipients in pharmaceutical formulations isknown in the art. For example, conventional vehicles and carriersinclude without limitation oils (e.g., vegetable oils such as olive oiland sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g.,phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer'ssolution)}, and organic solvents (e.g., dimethyl sulfoxide and alcohols[e.g., ethanol, glycerol and propylene glycol]). Except insofar as anyconventional excipient or carrier is incompatible with a peptideproduct, the disclosure encompasses the use of conventional excipientsand carriers in formulations containing a peptide product. See, e.g.,Remington: The Science and Practice of Pharmacy, 21st Ed., LippincottWilliams & Wilkins (Philadelphia, Pa.) (2005); Handbook ofPharmaceutical Excipients, 5th Ed., Rowe et ah, Eds., The PharmaceuticalPress and the American Pharmaceutical Association (2005); Handbook ofPharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower PublishingCo. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson,Ed., CRC Press (Boca Raton, Fla.) (2004). The appropriateness of aparticular formulation can depend on various factors, such as the routeof administration chosen. Potential routes of administration of apharmaceutical composition comprising the compounds or the likedisclosed herein can include, without limitation oral, parenteral(including intradermal, subcutaneous, intramuscular, intravascular,intravenous, intra-arterial, intraperitoneal, intracavitary andtopical), topical (including transdermal, transmucosal, intranasal(e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary(e.g., by oral or nasal inhalation), buccal, sublingual, rectal (e.g.,by suppository), vaginal (e.g., by suppository), and/or other suitableroute.

The term “therapeutically effective amount” refers to an amount of acompound that, when administered to a subject, is sufficient to prevent,reduce the risk of developing, delay the onset of, slow the progressionof or cause regression of the medical condition being treated, or toalleviate to some extent the medical condition or one or more symptomsor complications of that condition, at least in some fraction of thesubjects taking that compound. The term “therapeutically effectiveamount” also refers to an amount of a compound that is sufficient toelicit the biological or medical response of a cell, tissue, organ orhuman which is sought by a medical doctor or clinician. The terms“treat,” “treating” and “treatment” include alleviating, ameliorating,inhibiting the progress of, reversing or abrogating a medical conditionor one or more symptoms or complications associated with the condition,and alleviating, ameliorating or eradicating one or more causes of thecondition. Reference to “treatment” of a medical condition includesprevention of the condition. The terms “prevent”, “preventing” and“prevention” include precluding, reducing the risk of developing anddelaying the onset of a medical condition or one or more symptoms orcomplications associated with the condition. The term “medicalconditions” (or “conditions” for brevity) includes diseases anddisorders. The terms “diseases” and “disorders” are used interchangeablyherein.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components). The singular forms “a,” “an,” and “the”include the plurals unless the context clearly dictates otherwise. Thesymbol “=” when used in describing a formula means “is”. The term“including” is used to mean “including but not limited to “Including”and “including but not limited to” are used interchangeably. The term“agent” is used herein to denote a chemical compound (such as an organicor a mixture of chemical compounds). Agents include, for example, agentsthat are known with respect to structure, and their orexin antagonistactivities of such agents may render them suitable as “therapeuticagents” in the methods and compositions disclosed herein. In addition,those of ordinary skill in the art recognize that it is common to usethe following abbreviations; which may have been used herein and aredefined as follows:

-   -   Me: methyl    -   Et: ethyl    -   t-Bu: tert-butyl    -   Ar: aryl    -   Ph: phenyl    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   Bn: benzyl    -   Ac: acetyl    -   Boc: tert-butyloxy carbonyl    -   BSA: bovine serum albumin    -   CbzCl: benzylchloroformate    -   CDI: carbonyl diimidazole    -   DCM: dichloromethane    -   DCE: dichloroethane    -   DEAD: diethylazodicarboxylate    -   DIPEA: N, N-diisopropylethylamine    -   DMF: N, N-dimethylformamide    -   DMSO: dimethylsulfoxide    -   CH₂Cl₂: dichloromethane

-   EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide    -   Et₃N: triethylamine    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   HCl: hydrogen chloride    -   HOAt: 1-hydroxy-7-aza-10-benzotriazole    -   HOBT: hydroxybenzotriazole hydrate    -   LCMS: Liquid Chromatography Mass Spectrometry    -   HPLC: High Performance Liquid Chromatography    -   Hunig's base: N,N-diisopropylethylamine    -   MeOH: methanol    -   MgSO₄: magnesium sulfate    -   MTBE: methyl tert-butyl ether    -   NaHCO₃: sodium bicarbonate    -   Na₂CO₃: sodium carbonate    -   K₂CO₃: potassium carbonate    -   NaOH: sodium hydroxide    -   NM M: N-methylmorpholine    -   PtO₂: Platinum oxide    -   Pd: Palladium    -   Pd/C: Palladium over carbon    -   PyClu:        1-(chloro-1pyrrolidinylmethylene)pyrrolidiniumhexafluorophosphate    -   RT or rt: room temperature    -   SOCl₂: thionyl chloride    -   THF: tetrahydrofuran    -   TFA: trifluoroacetic acid    -   X-Phos: 2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl    -   HATU:        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   NMR: Nuclear Magnetic Resonance    -   ESI: Electrospray Ionization    -   MS: Mass spectrometry    -   reaction: reaction

All references cited within this disclosure are hereby incorporated byreference in their entirety. Certain embodiments are further describedin the following examples. These embodiments are provided as examplesonly and are not intended to limit the scope of the claims in any way.

EXAMPLES I. General Synthetic Methods & Procedures A. General

All temperatures are stated in ° C. Commercially available startingmaterials were used as received without further purification. Unlessotherwise specified, all reactions were carried out in oven-driedglassware under an atmosphere of nitrogen. Compounds were purified byflash column chromatography on silica gel or by preparative HPLC.Compounds described in the invention are characterized by LC-MS data(retention time t_(R) is given in min; molecular weight obtained fromthe mass spectrum is given in g/mol) using the conditions listed below.

LC-MS Under Acidic Conditions

Method A: Agilent 1100 series with mass spectrometry detection (MS:Agilent single quadrupole). Column: Zorbax SB (3.5 μm, 4.6×150 mm).Conditions: MeCN (0.1% FA) [gradient eluent A]; water (0.1% FA)[gradient eluent B]. Gradient: 95% B+5% B over 5 min (flow: 0.8 ml/min).Detection: UV 280/254 nm+MS.Method B: Agilent 1100 series with mass spectrometry detection (MS:Agilent single quadrupole). Column: X-Bridge C18 (3.5 μm, 4.6×150 mm).Conditions: MeCN (0.1% FA) [gradient eluent A]; water (0.1% FA)[gradient eluent B]. Gradient: 95% B+5% B over 5 min (flow: 0.8 ml/min).Detection: UV 280/254 nm+MS.In general, the compounds of this invention may be prepared by methodsknown to those skilled in the art and contemporary technologies in thefield. Schemes 1˜4 below illustrate synthetic routes to the compounds ofthe present invention. Other equivalent schemes, which will be readilyapparent to the ordinary skilled synthetic organic or medicinal chemistmay alternatively be used to synthesize various portions of themolecules as illustrated by the general schemes described herein.

B. Intermediates Synthesis 1. Synthesis of Intermediate A

Step 1: Synthesis of Compound A1:Ethyl-3-Phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) wasdissolved in Acetone (10.0 mL). The K₂CO₃ (0.96 g, 6.9 mmol) was added,followed by 1-Bromo-2-Chloro-ethane (0.1 mL, 11.6 mmol). The reactionmixture was heated at 55° C. for 16 h. LCMS data shows desired productformation m/z 279.0 and minor amount of side product formation. Thereaction mixture was filtered and the solid was washed with ethylacetate. The filtrate was concentrated under reduced pressure to obtaincrude product. The crude product was purified by column chromatography,Mobile Phase: EtOAc:Hexane, gradient. The 0.6 g of liquid product wasisolated (Yield 93.2%). MS (ESI) mass calcd. for C₁₄H₁₅ClN₂O₂, 278.7;m/z found 279.0 [M+H]⁺Step 2: Synthesis of Compound A2; Compound A1 (0.55 g, 1.97 mmol) wasdissolved in dry THF (6.0 mL). The DIBAL (12.0 mL, 1.0 M solution, 11.8mmol) was added, under ice cooling bath. The reaction mixture wasgradually warmed to room temperature and stirred for 16 h. LCMS datashows desired product formation m/z 237.0. The reaction mixture wasquenched with 1.0 N aq. NaOH solution and diluted with ethyl acetate(10.0 mL). The reaction mixture was filtered through celite bed andwashed with ethyl acetate (10.0 mL×3). The EtOAc layer was separated andwashed with water followed by brine. The organic layer was dried overanhydrous sodium sulfate. The evaporation of solvent gave crude product0.4 g (Yield 85.6%). MS (ESI) mass calcd. for C₁₂H₁₃ClN₂O, 236.7; m/zfound 237.0 [M+H]⁺Step 3: Synthesis of Compound A3: Compound A2 (0.47 g, 1.97 mmol) wasdissolved in dry DMF (12.0 mL). The NaH (0.12 g, 2.96 mmol) was addedunder ice cooling. The reaction mixture was gradually warmed to roomtemperature and stirred for 16 h. LCMS data shows desired productformation m/z 201.1. The reaction mixture was diluted with water and theproduct was extracted with ethyl acetate. The combined ethyl acetatelayer was separated and dried over anhydrous sodium sulfate. Theevaporation of solvent gave crude product. The crude product waspurified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient.The 0.26 g of solid product was obtained (Yield 65.3%). MS (ESI) masscalcd. for C₁₂H₁₂N₂O, 200.2; m/z found 201.1 [M+H]⁺Step 4: Synthesis of Compound A4: Compound A3 (0.25 g, 1.25 mmol) wasdissolved in DCM (5.0 mL). The NBS (0.24 g, 1.37 mmol) was added, andreaction mixture was stirred at room temperature for 16 h. LCMS datashows desired product formation m/z 280.9. The evaporation of solventgave crude product. The crude product was purified by columnchromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.29 g ofliquid product was obtained (Yield 81.7%). MS (ESI) mass calcd. forC₁₂H₁₁BrN₂O, 279.1; m/z found 280.9 [M+H]⁺Step 5: Synthesis of Intermediate A: Compound A4 (0.025 g, 0.09 mmol)was dissolved in anhydrous THF (1.0 mL) under N₂ atm. The reactionmixture was cooled at −78.0° C. temperature and n-BuLi (0.12 mL, 1.6 M)was added into the reaction mixture. The reaction mixture was stirred at−78.0° C. temperature for 30.0 min. The dry CO₂ gas was bubbled throughthe reaction mixture at −65° C. and the reaction mixture was graduallywarmed at room temperature. The LCMS data shows desired productformation m/z 245, debrominated side product (m/z 201) and some unknownproduct formation. The reaction mixture was quenched by water andextracted with ethyl acetate. The ethyl acetate layer was separated anddebrominated product was recovered. The aq. Layer was acidified with 1 MHCl solution and evaporated to dryness to obtain 0.022 g of solidproduct. MS (ESI) mass calcd. for C₁₃H₁₂N₂O₃, 244.3; m/z found 245.0[M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.06-4.15 (m, 2H) 4.16-4.25(m, 2H) 5.03-5.10 (s, 2H) 7.32-7.40 (m, 3H) 7.60-7.69 (m, 2H).

2. Synthesis of Intermediate B

Step 1: Synthesis of Compound B1: 2-Chloro-5-trifluoromethyl-pyridine(0.33 g, 1.82 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.36 g,1.81 mmol) were dissolved in dry DMSO (5.0 mL). The DIPEA (1.6 mL, 9.1mmol) was added and reaction mixture was stirred at 100° C. temperaturefor 4 h. TLC shows product formation. The reaction mixture was dilutedwith water. The product was extracted with Ethyl acetate. The combinedethyl acetate layer was washed with water followed by brine. The organiclayer was separated and dried over anhydrous sodium sulfate. Theevaporation of solvent gave crude product. The crude product waspurified by ISCO combi-flash chromatography system, Mobile phase:EtOAc:Hexane gradient. The desired liquid product was isolated 0.24 g(Yield 39.0%). MS (ESI) mass calcd. for C₁₆H₂₂F₃N₃O₂, 345.0; m/z found346.1 [M+H]⁺

Step 2: Synthesis of Intermediate B: Compound B1 (0.24 g, 0.71 mmol)were dissolved in dry Dioxane (3.0 mL). The 4.0 M HCl solution indioxane (1.77 mL, 7.08 mmol) was added and reaction mixture was stirredat 50° C. temperature for 4 h. LCMS shows product formation m/z 246. Thereaction mixture was concentrated under reduced pressure to obtain solidproduct (0.19 g, Yield 78.4%). MS (ESI) mass calcd. for C₁₁H₁₄F₃N₃,245.2; m/z found 246.0 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.76-2.01 (m, 1H) 2.01-2.15 (m, 1H) 2.15-2.28 (m, 1H) 2.36 (br s, 1H)3.25-3.46 (br s, 1H) 3.48 (br s, 1H) 4.04 (br s, 2H) 4.31 (br s, 1H)7.47 (br s, 1H) 7.86 (br s, 1H) 8.19 (br s, 1H) 9.41-10.42 (br s, 1H).

3. Synthesis of Intermediate C

Step 1: Synthesis of Compound Cl: 2-Chloro-5-ethyl-pyrimidine (0.2 g,1.37 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.28 g, 1.37 mmol)were dissolved in dry DMF (5.0 mL). The Cs₂CO₃ (0.89 g, 2.75 mmol) wasadded and reaction mixture was stirred at 120° C. temperature for 24 h.TLC shows product formation. The reaction mixture was diluted withwater. The product was extracted with Ethyl acetate. The combined ethylacetate layer was washed with water followed by brine. The organic layerwas separated and dried over anhydrous sodium sulfate. The evaporationof solvent gave crude product. The crude product was purified by ISCOcombi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient.The desired liquid product was isolated 0.27 g (Yield 64.2%). MS (ESI)mass calcd. for C₁₆H₂₆N₄O₂, 306.4; m/z found 307.1 [M+H]⁺.Step 2: Synthesis of Intermediate C: Compound Cl (0.27 g, 0.88 mmol)were dissolved in dry Dioxane (3.0 mL). The 4.0 M HCl solution indioxane (2.2 mL, 8.81 mmol) was added and reaction mixture was stirredat 60° C. temperature for 4 h. LCMS shows product formation m/z 207. Thereaction mixture was concentrated under reduced pressure to obtain solidproduct (0.31 g, Yield Quant.). MS (ESI) mass calcd. for C₁₁H₁₈N₄,206.3; m/z found 207.1 [M+H]⁺.

4. Synthesis of Intermediate D

Step 1: Synthesis of Compound D1:[(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine(0.35 g, 1.4 mmol) and 2-chloro-5-ethyl-pyrimidine (0.2 g, 1.4 mmol)were dissolved in dry DMF (4.0 mL). The K₂CO₃ (0.39 g, 2.82 mmol) wasadded and reaction mixture was stirred at 120° C. temperature for 6 h.TLC shows product formation. The reaction mixture was diluted withwater. The product was extracted with Ethyl acetate. The combined ethylacetate layer was washed with water followed by brine. The organic layerwas separated and dried over anhydrous sodium sulfate. The evaporationof solvent gave crude product. The crude product was purified byCombiflash chromatography system, Mobile phase: EtOAc:Hexane, gradient.The 0.33 g of product was obtained (Yield 65.4%). MS (ESI) mass calcd.for C₂₁H₃₀N₄O, 354.5; m/z found 355.2 [M+H]⁺, ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.85-0.94 (d, J=8.0 Hz, 3H) 1.16 (t, J=8.0 Hz, 3H)1.25-1.47 (m, 2H) 1.50-1.84 (m, 2H) 2.05-2.25 (m, 1H) 2.35-2.47 (q,J=8.0 Hz, 2H) 2.47-2.60 (m, 1H) 2.62-2.83 (m, 2H) 3.33-3.46 (m, 2H) 3.77(s, 3H) 3.78-3.85 (m, 2H) 5.68 (br s, 1H) 6.84 (d, J=8.66 Hz, 2H)7.24-7.31 (m, 2H) 8.12 (s, 2H). Step 2: Synthesis of Intermediate D:Compound 01 (0.1 g, 0.3 mmol) was dissolved in MeOH (3.0 mL). The 20.0%Pd—OH/C (30.0 mg) was added and reaction mixture was stirred at ambienttemperature for 24 h. The TLC shows little amount of starting materialand product formation. The 20.0% Pd—OH/C (30.0 mg) was further added andreaction mixture was stirred at ambient temperature for another 24 h.The TLC shows completion of reaction. The LCMS data shows m/z 235 ofproduct formation. The reaction mixture was filtered over celite andwashed with MeOH. The filtrate was evaporated under reduced pressure toobtain 66.0 mg of crude product. The crude product is used in next stepwithout purification. MS (ESI) mass calcd. for C₁₃H₂₂N₄, 234.3; m/zfound 235.2 [M+H]⁺.

5. Synthesis of Intermediate E

Step 1: Synthesis of Compound E1:[(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine(0.32 g, 1.29 mmol) and 2-chloro-5-trifluoromethyl-pyridine (0.23 g,1.29 mmol) were dissolved in dry DMF (5.0 mL). The K₂CO₃ (0.36 g, 2.58mmol) was added and reaction mixture was stirred at 120° C. temperaturefor 4 h. TLC shows product formation and LCMS shows m/z 394 of productformation. The reaction mixture was diluted with water. The product wasextracted with Ethyl acetate. The combined ethyl acetate layer waswashed with water followed by brine. The organic layer was separated anddried over anhydrous sodium sulfate. The evaporation of solvent gavecrude product. The crude product was purified by ISCO combiflashchromatography system, Mobile phase: DCM:MeOH (90:10 v/v mL). Theproduct band was isolated. The 0.41 g of pure product was obtained withm/z 394 (Yield 81.4%). MS (ESI) mass calcd. For C₂₁H₂₆F₃N₃O, 393.5; m/zfound 394.1 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (d, J=7.04Hz, 3H) 1.19-1.46 (m, 2H) 1.54-1.65 (m, 1H) 1.65-1.83 (m, 1H) 2.07-2.22(m, 1H) 2.50-2.65 (m, 1H) 2.65-2.80 (m, 2H) 3.20-3.38 (m, 2H) 3.78 (s,3H) 3.79-3.84 (m, 2H) 5.67 (br s, 1H) 6.32 (d, J=8.80 Hz, 1H) 6.80-6.89(m, 2H) 7.15-7.29 (m, 2H) 7.49 (dd, J=8.80, 2.35 Hz, 1H) 8.28-8.32 (m,1H).Step 2: Synthesis of Intermediate E: Compound E1 (0.02 g, 0.5 mmol) wasdissolved in MeOH (5.0 mL). The 10.0% Pd/C (60.0 mg) was added andreaction mixture was stirred at ambient temperature for 24 h under H₂atm. The TLC shows completion of reaction. The LCMS data shows m/z 274of product formation. The reaction mixture was filtered over celite andwashed with MeOH. The filtrate was evaporated under reduced pressure toobtain 0.16 g of crude product. MS (ESI) mass calcd. for C₁₃H₁₈F₃N₃,273.3; m/z found 274.1 [M+H]⁺.

6. Synthesis of Intermediate F

Step 1: Synthesis of Compound F1: The N-Boc-L-Prolinol (0.5 g, 2.48mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) wasadded followed by DMAP (0.61 g, 4.97 mmol). The reaction mixture wascooled in ice bath and p-TsCl (0.52 g, 2.73 mmol) was added. Thereaction mixture was stirred and gradually warmed to room temperaturefor 16 h. The LCMS shows product formation m/z 256, 300. The reactionmixture was diluted with water. The product was extracted with DCM. TheDCM layer was separated and dried over anhydrous Na₂SO₄. The evaporationof solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd.for C₁₇H₂₅NO₅S, 355.5; m/z found 300.1, 256.1 [M+H]⁺.

Step 2: Synthesis of Compound F2: Compound F1 (0.88 g, 2.48 mmol) and3-Phenyl-1H-Pyrazole (0.43 g, 2.98 mmol) were dissolved in dry DMF (5.0mL). The Cs₂CO₃ (1.61 g, 4.96 mmol) was added and the reaction mixturewas stirred at 70° C. temperature for 4 h. The LCMS shows productformation m/z 328. The reaction mixture was cooled at ambienttemperature and diluted with water. The product was extracted with Ethylacetate. The EtOAc layer was separated and dried over anhydrous Na₂SO₄.The evaporation of solvent gave crude product. The crude product waspurified by column chromatography, Mobile phase: EtOAc:Hexane gradient.The 0.73 g of pure product was obtained (Yield 89.5%). MS (ESI) masscalcd. for C₁₉H₂₅N₃O₂, 327.4; m/z found 328.3 [M+H]⁺.Step 3: Synthesis of Intermediate F: Compound F2 (0.73 g, 2.24 mmol) wasdissolved in dry Dioxane (10.0 mL). The 4.0 M HCl solution in dioxane(2.8 mL, 11.2 mmol) was added and reaction mixture was stirred at 50° C.temperature for 16 h. LCMS shows product formation m/z 228. The reactionmixture was filtered and washed with Hexane (5.0 mL×3) to obtain the0.53 g of solid product (Yield Quant.). MS (ESI) mass calcd. forC₁₄H₁₇N₃, 227.1; m/z found 228.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.74-1.94 (m, 1H) 1.94-2.05 (m, 1H) 2.06-2.15 (m, 1H) 2.16-2.35(m, 1H) 3.21-3.45 (m, 2H) 4.33 (br s, 1H) 4.86 (dd, J=14.82, 3.96 Hz,1H) 5.07 (br dd, J=14.67, 8.66 Hz, 1H) 6.75 (d, J=2.20 Hz, 1H) 7.34-7.48(m, 3H) 7.76-7.87 (m, 2H) 8.44 (d, J=2.49 Hz, 1H) 9.51-10.12 (br, 1H).

7. Synthesis of Intermediate G

Step 1: Synthesis of Compound G1: N-Boc-L-Prolinol (0.2 g, 0.99 mmol)was dissolved in dry DMF (4.0 mL). The NaH (0.08 g, 2.0 mmol) was addedunder ice cooling. The 2-Chloro-5-Ethyl-Pyrimidine (0.2 g, 1.5 mmol) wasadded under cooling and reaction mixture was gradually warmed at roomtemperature under stirring for 3 h. The LCMS shows product formation m/z308.2. The reaction mixture was diluted with water. The product wasextracted with Ethyl acetate three times. The EtOAc layers wereseparated and dried over anhydrous Na₂SO₄. The evaporation of solventgave crude product. The crude product was purified by columnchromatography, Mobile phase: EtOAc:Hexane gradient. The 0.3 g of pureproduct was obtained (yield quantitative). MS (ESI) mass calcd. forC₁₆H₂₅N₃O₃, 307.4; m/z found 308.2 [M+H]⁺.Step 2: Synthesis of Intermediate G: HBS-037-152 (0.3 g, 0.99 mmol) weredissolved in dry Dioxane (4.0 mL). The 4.0 M HCl solution in dioxane(2.48 mL, 9.9 mmol) was added and reaction mixture was stirred at 60° C.temperature for 4 h. LCMS shows product formation m/z 208.1. Thereaction mixture was concentrated under reduced pressure to obtain 0.32g of liquid product. MS (ESI) mass calcd. for C₁₁H₁₇N₃O, 207.3; m/zfound 208.1 [M+H]⁺.

8. Synthesis of Intermediate H

Synthesis of Compound H1: N-Boc-L-Prolinol (0.2 g, 0.99 mmol) wasdissolved in dry DMF (4.0 mL). The NaH (0.08 g, 2.0 mmol) was addedfollowed by 2-Chloro-5-trifluoromethylpyridine (0.27 g, 1.5 mmol). Thereaction mixture was heated at 70° C. temperature for 3 h. The LCMSshows product formation m/z 347.1. The reaction mixture was diluted withwater. The product was extracted with Ethyl acetate three times. TheEtOAc layers were separated and dried over anhydrous Na₂SO₄. Theevaporation of solvent gave crude product. The crude product waspurified by column chromatography, Mobile phase: EtOAc: Hexane gradient.The 0.3 g of pure product was obtained (Yield 86.0%). MS (ESI) masscalcd. for C₁₆H₂₁F₃N₂O₃, 346.3; m/z found 347.1 [M+H]⁺.Synthesis of Intermediate H: Compound H1 (0.3 g, 0.86 mmol) weredissolved in dry Dioxane (2.0 mL). The 4.0 M HCl solution in dioxane(2.14 mL, 8.6 mmol) was added and reaction mixture was stirred at 60° C.temperature for 4 h. LCMS shows product formation m/z 247.1. Thereaction mixture was filtered and washed with Hexane (5.0 mL×3) toobtain the 0.27 g of solid product (Yield Quant.). MS (ESI) mass calcd.for C₁₁H₁₃F₃N₂O, 246.2; m/z found 247.1 [M+H]⁺, ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.87-1.99 (m, 1H) 1.99-2.08 (m, 1H) 2.08-2.17 (m,1H) 2.17-2.29 (m, 1H) 3.32-3.49 (m, 2H) 3.96-4.09 (m, 1H) 4.60-4.77 (m,2H) 7.00 (d, J=8.73 Hz, 1H) 7.77 (dd, J=8.73, 2.35 Hz, 1H) 8.37-8.42 (m,1H) 9.74 (br s, 1H) 10.32 (br s, 1H).

9. Synthesis of Intermediate I

Step 1: Synthesis of Compound 11: The ethyl benzoylacetate (0.5 g, 2.6mmol) was dissolved in DMSO (5.0 mL). The NBS (0.51 g, 2.86 mmol) wasadded and reaction mixture was stirred at ambient temperature for 24 h.LCMS shows product formation m/z 270.9. The reaction mixture was dilutedwith water and the product was extracted with ethyl acetate. The ethylacetate layer was separated and dried over anhydrous Na₂SO₄. Theevaporation of solvent gave crude product. The crude product waspurified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The0.42 g of product was obtained (Yield 59.7%). MS (ESI) mass calcd. forC₁₁H₁₁BrO₃, 271.1; m/z found 270.9 [M+H]⁺.Step 2: Synthesis of Compound 12: Compound 11 (0.42 g, 1.55 mmol) wasdissolved in anhydrous acetonitrile (5.0 mL). The 2-amino-pyridine (0.15g, 1.55 mmol) was added and reaction mixture was stirred at 80° C. for 1h. LCMS shows product formation m/z 267.1. The reaction mixture wasconcentrated under reduced pressure to yield crude product. The crudeproduct was purified by combi-flash system, Mobile phase: EtOAc:Hexanegradient. The 0.24 g of product was obtained (Yield 58.0%). MS (ESI)mass calcd. for C₁₆H₁₄N₂O₂, 266.3; m/z found 267.1 [M+H]⁺.Step 3: Synthesis of Intermediate I: Compound 12 (0.24 g, 0.9 mmol) wasdissolved in MeOH (5.0 mL). The 1.0 N aq. NaOH solution (4.51 mL, 4.51mmol) was added and reaction mixture was stirred at 60° C. temperaturefor 3 h. LCMS shows product formation m/z 239. The reaction mixture wasconcentrated under reduced pressure. The solid was dissolved in waterand acidified with 2.0 M aq. HCl solution (pH=5). The ppts were filteredand washed with water (10.0 mL×3) to obtain 0.2 g of solid product. MS(ESI) mass calcd. for C₁₄H₁₀N₂O₂, 238.2; m/z found 239.1 [M+H]⁺, ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.04 (t, J=6.93 Hz, 1H) 7.33-7.48 (m, 4H)7.70-7.78 (m, 3H) 9.41 (d, J=7.04 Hz, 1H).

10. Synthesis of Intermediate J

Synthesis of Intermediate J: Compound J1 (synthesized as reported inJournal of Medicinal Chemistry; 2011, 54 (13), 4752-4772) (0.2 g, 0.75mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. NaOH solution (3.8mL, 3.8 mmol) was added and reaction mixture was stirred at 60° C.temperature for 24 h. LCMS shows product formation m/z 239.1. Thereaction mixture was concentrated under reduced pressure. The solid wasdissolved in water and acidified with 1.0 M aq. HCl solution (pH=5). Theppts were filtered and washed with water (10.0 mL×3) to obtain 0.18 g ofsolid product. MS (ESI) mass calcd. for C₁₄H₁₀N₂O₂, 238.2; m/z found239.1 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.90-7.03 (m, 1H)7.27-7.47 (m, 4H) 7.75-7.78 (ddd, J=4.86, 3.21, 1.54 Hz, 2H) 8.18-8.28(dd, J=8.99, 0.70 Hz, 1H) 8.49-8.56 (dd, J=6.90, 0.73 Hz, 1H).

II. Synthesis of Example Compounds A. Example 1

Synthesis of Compound Example 1: Intermediate A (0.02 g, 0.082 mmol) wasdissolved in dry DMF (0.7 mL). The HATU (0.05 g, 0.12 mmol) was addedfollowed by DIPEA (0.06 mL, 0.33 mmol). The Intermediate F was added andreaction mixture was stirred at ambient temperature for 16 h. LCMS datashows product formation m/z 454. The reaction mixture was diluted withsaturated solution of NaHCO₃. The product was extracted with Ethylacetate. The combined ethyl acetate layer was washed with water followedby brine. The organic layer was separated and dried over anhydroussodium sulfate. The evaporation of solvent gave crude product. The crudeproduct was purified by prep-TLC plate, Mobile phase: EtOAc:Hexane(75:25 v/v mL). The desired bands were isolated to yield 0.009 g ofproduct (Yield 23.5%). MS (ESI) mass calcd. for C₂₇H₂₇N₅O₂, 453.5; m/zfound 454.1 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.57 (m,2H) 1.78-1.95 (m, 1H) 1.95-2.08 (m, 2H) 2.58 (dt, J=10.51, 7.40 Hz, 1H)2.98-3.23 (m, 1H) 3.64-3.92 (m, 1H) 4.02-4.27 (m, 3H) 4.32-4.54 (m, 2H)4.54-4.71 (m, 1H) 4.87-5.05 (m, 1H) 6.50-6.62 (m, 1H) 7.23-7.42 (m, 6H)7.47 (d, J=2.20 Hz, 1H) 7.51-7.61 (m, 2H) 7.66-7.86 (m, 2H).

B. Example 2

Synthesis of Compound Example 2: Intermediate A (0.034 g, 0.14 mmol) wasdissolved in dry DMF (1.5 mL). The HATU (0.05 g, 0.14 mmol) was addedfollowed by DIPEA (0.12 mL, 0.7 mmol). The Intermediate B (0.025 g, 0.07mmol) was added and reaction mixture was stirred at ambient temperaturefor 16 h. LCMS data shows product formation m/z 472. The reactionmixture was diluted with saturated solution of NaHCO₃. The product wasextracted with Ethyl acetate. The combined ethyl acetate layer waswashed with water followed by brine. The organic layer was separated anddried over anhydrous sodium sulfate. The evaporation of solvent gavecrude product. The crude product was purified by prep-TLC plate, Mobilephase: EtOAc:Hexane (75:25 v/v mL). The desired product band wasisolated. The 13.0 mg of pure product was obtained (Yield 39.0%). MS(ESI) mass calcd. for C₂₄H₂₄F₃N₅O₂, 471.5; m/z found 472.1 [M+H]⁺, ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.52-1.77 (m, 3H) 1.96-2.21 (m, 1H)2.57-2.71 (m, 1H) 3.16-3.28 (m, 1H) 3.45-3.59 (m, 2H) 4.09-4.29 (m, 4H)4.60-4.81 (m, 1H) 4.84-4.94 (d, J=15.70 Hz, 1H) 5.01 (d, J=15.70 Hz, 1H)6.56 (br d, J=8.80 Hz, 2H) 7.22-7.36 (m, 3H) 7.49-7.58 (m, 3H) 7.99-8.32(br s, 1H).

C. Example 3

Synthesis of Compound Example 3: Intermediate A (0.025 g, 0.1 mmol) wasdissolved in dry DMF (0.7 mL). The HATU (0.08 g, 0.2 mmol) was addedfollowed by DIPEA (0.18 mL, 1.0 mmol). Intermediate C (0.036 g, 0.1mmol) was dissolved in dry DMF (1.0 mL) and added to reaction mixture.The reaction mixture was stirred at ambient temperature for 16 h. LCMSdata shows product formation m/z 433. The reaction mixture was dilutedwith saturated solution of NaHCO₃. The product was extracted with Ethylacetate. The combined ethyl acetate layer was washed with water followedby brine. The organic layer was separated and dried over anhydroussodium sulfate. The evaporation of solvent gave crude product. The crudeproduct was purified by prep-TLC plate, Mobile phase: EtOAc. The desiredproduct band was isolated to obtain 0.02 g of pure product (Yield46.0%). MS (ESI) mass calcd. for C₂₄H₂₈N₆O₂, 432.5; m/z found 433.1[M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12-1.25 (t, J=8.0 Hz, 3H)1.37-1.65 (m, 2H) 1.52-2.18 (m, 1H) 2.36-2.49 (m, 2H) 2.49-2.74 (m, 1H)2.82-3.25 (m, 1H) 3.43-3.86 (m, 2H) 3.90-4.30 (m, 5H) 4.47-4.64 (m, 1H)4.75-5.13 (m, 2H) 6.02 (br t, J=4.58 Hz, 1H) 7.25-7.39 (m, 3H) 7.39-7.59(m, 2H) 7.98-8.17 (br s, 2H).

D. Example 4

Synthesis of Compound Example 4: Intermediate J (0.046 g, 0.192 mmol)was dissolved in dry DCM (2.0 mL). The EDC.HCl (0.049 g, 0.26 mmol) andHOBt (0.035 g, 0.26 mmol) were added followed by Et₃N (0.1 mL, 0.6mmol). Intermediate D (0.03 g, 0.13 mmol) was dissolved in dry DCM (1.0mL) and added to the reaction mixture. The reaction mixture was stirredat ambient temperature for 16 h. LCMS data shows product formation withm/z 455. The reaction mixture was diluted with saturated solution ofNaHCO₃. The product was extracted with Ethyl acetate. The combined ethylacetate layer was washed with water followed by brine. The organic layerwas separated and dried over anhydrous sodium sulfate. The evaporationof solvent gave crude product. The crude product was purified byprep-TLC plate, Mobile phase: DCM:MeOH (97:03 v/v mL). The desiredproduct band was isolated to obtain 0.027 g of product (Yield 31.3%). MS(ESI) mass calcd. for C₂₇H₃₀N₆O, 454.6; m/z found 455.2 [M+H]⁺, ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 0.52-0.54 (d, J=4.0 Hz, 1H) 1.02-1.03 (d,J=4.0 Hz, 2H) 1.08-1.19 (m, 4H) 1.19-1.47 (m, 3H) 1.59-1.91 (m, 1H)2.23-2.33 (m, 1H) 2.42 (q, J=7.58 Hz, 1H) 2.67-2.94 (m, 1H) 3.06-3.51(m, 2H) 3.73-4.11 (m, 1H) 4.46-5.09 (m, 1H) 5.16-5.78 (m, 1H) 6.62-6.83(m, 1H) 7.05-7.15 (m, 1H) 7.27-7.45 (m, 3H) 7.59-7.77 (m, 4H) 8.08-8.14(m, 1H) 8.19-8.42 (d, J=6.97 Hz, 1H).

E. Example 5

Synthesis of Compound Example 5: Intermediate A (0.025 g, 0.1 mmol) wasdissolved in dry DCM (2.0 mL). The EDC.HCl (0.039 g, 0.21 mmol) and HOBt(0.028 g, 0.21 mmol) were added followed by Et₃N (0.07 mL, 0.5 mmol).Intermediate D (0.024 g, 0.1 mmol) was dissolved in dry DCM (1.0 mL) andadded to the reaction mixture. The reaction mixture was stirred atambient temperature for 16 h. LCMS data shows product formation m/z 461.The reaction mixture was concentered and diluted with saturated solutionof NaHCO₃. The product was extracted with Ethyl acetate. The combinedethyl acetate layer was washed with water followed by brine. The organiclayer was separated and dried over anhydrous sodium sulfate. Theevaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: DCM:MeOH (97:03 v/v mL). Thedesired product band was isolated to obtain 25.4 mg of product (Yield53.9%). MS (ESI) mass calcd. for C₂₆H₃₂N₆O₂, 460.6; m/z found 461.2[M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (d, J=7.04 Hz, 1H)0.98 (d, J=7.04 Hz, 2H) 1.16 (td, J=7.57, 5.98 Hz, 4H) 1.20-1.41 (m, 2H)1.53-1.85 (m, 1H) 2.42 (qd, J=7.57, 2.24 Hz, 2H) 2.70 (tdd, J=13.35,13.35, 5.06, 3.15 Hz, 1H) 3.13-3.52 (m, 2H) 3.75-4.00 (m, 2H) 4.00-4.19(m, 3H) 4.36-4.72 (m, 1H) 4.74-4.94 (m, 2H) 5.03 (dt, J=12.10, 4.29 Hz,1H) 5.53 (br d, J=4.84 Hz, 1H) 7.24-7.39 (m, 3H) 7.46-7.60 (m, 2H) 8.04(s, 1H) 8.10 (s, 1H).

F. Example 6

Synthesis of Compound Example 6: Intermediate J (0.017 g, 0.1 mmol) wasdissolved in dry DCM (2.0 mL). The EDC.HCl (0.03 g, 0.15 mmol) and HOBt(0.02 g, 0.15 mmol) were added followed by Et₃N (0.05 mL, 0.4 mmol).Intermediate E (0.02 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL) andadded to the reaction mixture. The reaction mixture was stirred atambient temperature for 16 h. LCMS data shows product formation m/z 494.The reaction mixture was concentered and diluted with saturated solutionof NaHCO₃. The product was extracted with Ethyl acetate. The combinedethyl acetate layer was washed with water followed by brine. The organiclayer was separated and dried over anhydrous sodium sulfate. Theevaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: EtOAc:Hexane (50:50 v/v mL).The desired product band was isolated to obtain 0.018 g of product(Yield 50.6%). MS (ESI) mass calcd. for C₂₇H₂₆F₃N₅O, 493.5; m/z found494.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (br d, J=4.99Hz, 1H) 1.05 (d, J=4.0 Hz, 2H) 1.16-1.52 (m, 3H) 1.57-1.98 (m, 2H)2.60-3.01 (m, 1H) 3.12-3.59 (m, 2H) 3.74-4.22 (m, 1H) 4.43-5.25 (m, 1H)5.55-6.10 (m, 1H) 6.45-6.47 (d, J=8.0 Hz, 1H) 6.65-6.89 (m, 1H)6.98-7.21 (m, 1H) 7.26-7.60 (m, 5H) 7.63-7.74 (m, 2H) 7.97-8.31 (br s,1H) 8.18-8.45 (br d, 1H).

G. Example 7

Synthesis of Compound Example 7: Intermediate A (0.025 g, 0.1 mmol) wasdissolved in dry DCM (2.0 mL). The EDC.HCl (0.04 g, 0.2 mmol) and HOBt(0.028 g, 0.2 mmol) were added followed by Et₃N (0.14 mL, 1.0 mmol).Intermediate E (0.024 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL) andadded to the reaction mixture. The reaction mixture was stirred atambient temperature for 16 h. LCMS data shows product formation m/z 500.The reaction mixture was concentrated and diluted with saturatedsolution of NaHCO₃. The product was extracted with Ethyl acetate. Thecombined ethyl acetate layer was washed with water followed by brine.The organic layer was separated and dried over anhydrous sodium sulfate.The evaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: EtOAc:Hexane (50:50 v/v mL).The desired product band was isolated to obtain 0.027 g of product(Yield 52.8%). MS (ESI) mass calcd. for C₂₆H₂₈F₃N₅O₂, 499.5; m/z found500.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.48-0.57 (d, J=8.0Hz, 1H) 1.00-1.01 (d, J=4.0 Hz, 2H) 1.06-1.46 (m, 4H) 1.62-1.80 (m, 1H)2.59-2.81 (m, 1H) 3.20-3.45 (m, 2H) 3.74-4.03 (m, 2H) 4.05-4.26 (m, 3H)4.37-5.08 (m, 3H) 5.67-5.81 (m, 1H) 5.95-6.43 (d, J=8.0 Hz, 1H)7.22-7.46 (m, 3H) 7.46-7.55 (m, 3H) 8.16-8.36 (s, 1H).

H. Example 8

Synthesis of Compound Example 8:2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I)(0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). The EDC.HCl(0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added followed byEt₃N (0.07 mL, 0.5 mmol). Intermediate E (0.03 g, 0.11 mmol) wasdissolved in dry DCM (2.0 mL) and added to the reaction mixture. Thereaction mixture was stirred at ambient temperature for 16 h. LCMS datashows product formation m/z 494.2. The reaction mixture was diluted withDCM and washed with saturated solution of NaHCO₃. The DCM layer wasseparated and dried over anhydrous Na₂SO₄. The evaporation of solventgave crude product. The crude product was purified by prep-TLC plate,Mobile phase: EtOAc:Hexane (30:70 v/v mL). The desired product band wasisolated to obtain 24.5 mg of desired product (Yield 47.3%). MS (ESI)mass calcd. for C₂₇H₂₆F₃N₅O, 493.5; m/z found 494.2 [M+H]⁺, ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 0.55-1.12 (d, 3H) 1.13-1.58 (m, 2H) 1.65-2.43(m, 2H) 2.69-3.1 (m, 1H) 3.12-3.35 (m, 1H) 3.35-3.51 (m, 1H) 3.73-4.64(m, 2H) 4.76-5.32 (m, 1H) 5.71 (br d, J=8.51 Hz, 1H) 6.51 (d, J=8.66 Hz,1H) 6.63-6.85 (m, 1H) 6.99-7.20 (m, 1H) 7.20-7.48 (m, 4H) 7.52-7.58 (m,1H) 7.61-7.77 (m, 2H) 7.85-8.24 (m, 1H) 8.28 (br d, J=6.90 Hz, 1H).

I. Example 9

Synthesis of Compound Example 9:2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I) (0.02g, 0.08 mmol) was dissolved in dry DCM (2.0 mL). The EDC.HCl (0.032 g,0.17 mmol) and HOBt (0.023 g, 0.17 mmol) were added followed by Et₃N(0.12 mL, 0.8 mmol). Intermediate D (0.02 g, 0.08 mmol) was dissolved indry DCM (2.0 mL) and added to the reaction mixture. The reaction mixturewas stirred at ambient temperature for 16 h. LCMS data shows productformation m/z 455. The reaction mixture was diluted with DCM and washedwith saturated solution of NaHCO₃. The DCM layer was separated and driedover anhydrous Na₂SO₄. The evaporation of solvent gave crude product.The crude product was purified by prep-TLC plate, Mobile phase:EtOAc:MeOH (98:2.0 v/v mL). The 21.2 mg of pure product was obtained(Yield 55.5%). MS (ESI) mass calcd. for C₂₇H₃₀N₆O, 454.6; m/z found455.3 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50-0.57 (m, 2H)0.97-1.22 (m, 4H) 1.22-1.50 (m, 2H) 1.55-1.94 (m, 2H) 2.25 (dquin,J=14.88, 7.39, 7.39, 7.39, 7.39 Hz, 2H) 2.35-2.59 (m, 1H) 2.75-2.92 (m,1H) 2.99-3.41 (m, 2H) 4.11-4.64 (m, 1H) 4.83-5.25 (m, 1H) 6.69-6.81 (m,1H) 7.06-7.17 (m, 1H) 7.17-7.29 (m, 1H) 7.29-7.44 (m, 3H) 7.55-7.68 (m,2H) 7.72 (br d, J=6.82 Hz, 1H) 8.09 (br d, J=5.72 Hz, 1H) 8.31 (d,J=6.90 Hz, 1H).

J. Example 10

Synthesis of Compound Example 10: Intermediate J (0.03 g, 0.13 mmol) wasdissolved in dry DCM (2.0 mL). The EDC.HCl (0.049 g, 0.25 mmol) and HOBt(0.034 g, 0.25 mmol) were added followed by DIPEA (0.2 mL, 1.23 mmol).Intermediate B (0.045 g, 0.13 mmol) was dissolved in dry DCM (2.0 mL)and added to the reaction mixture. The reaction mixture was stirred atambient temperature for 16 h. LCMS data shows product formation m/z 466.The reaction mixture was diluted with DCM and washed with saturatedsolution of NaHCO₃. The DCM layer was separated and dried over anhydrousNa₂SO₄. The evaporation of solvent gave crude product. The crude productwas purified by prep-TLC plate, Mobile phase: EtOAc:Hexane (50:50 v/vmL). The desired product band was isolated to obtain 0.052 g of product(Yield 88.2%). MS (ESI) mass calcd. for C₂₅H₂₂F₃N₅O, 465.5; m/z found466.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-2.02 (m, 4H)2.59-2.73 (m, 1H) 3.06-3.29 (m, 1H) 3.47-3.63 (m, 2H) 4.66-4.86 (m, 1H)6.48-6.65 (d, J=8.0 Hz 1H) 6.65-6.78 (br s, 1H) 6.86 (br t, J=6.75 Hz,1H) 7.17-7.44 (m, 4H) 7.44-7.62 (m, 1H) 7.62-7.72 (m, 3H) 8.33 (br s,1H) 8.47 (br d, J=6.90 Hz, 1H).

K. Example 11

Synthesis of Compound Example 11:2-Phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I)(0.024 g, 0.1 mmol) was dissolved in mixture of dry THF:DMF (2.0 mL,1:1). The HATU (0.038 g, 0.1 mmol) was added followed by DIPEA (0.05 g,0.4 mmol). Intermediate B (0.032 g, 0.1 mmol) was added to the reactionmixture. The reaction mixture was stirred at ambient temperature for 16h. LCMS data shows product formation m/z 466. The reaction mixture wasdiluted with saturated solution of NaHCO₃ and extracted with Ethylacetate. The ethyl acetate layer was separated and dried over anhydrousNa₂SO₄. The evaporation of solvent gave crude product. The crude productwas purified by prep-TLC plate, Mobile phase: EtOAc:Hexane (75:25 v/vmL). The desired product band was isolated to obtain 0.01 g of product(Yield 20.0%). MS (ESI) mass calcd. for C₂₅H₂₂F₃N₅O, 465.5; m/z found465.9 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-2.04 (m, 4H)2.60 (br s, 1H) 3.09-3.34 (m, 1H) 3.51-3.66 (m, 2H) 4.78 (br s, 1H)6.33-6.51 (br s, 1H) 6.58 (br d, J=8.51 Hz, 1H) 6.90 (br t, J=6.60 Hz, 1H) 7.26-7.46 (m, 4H) 7.49-7.61 (br d, J=8.0 Hz, 1H) 7.61-7.71 (m, 3H)8.35 (br s, 1H) 8.58 (br d, J=5.80 Hz, 1H).

L. Example 12

Synthesis of Compound Example 12:2-Phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I)(0.036 g, 0.15 mmol) was dissolved in dry THF (2.5 mL). The HATU (0.058g, 0.15 mmol) was added followed by DIPEA (0.078 g, 0.6 mmol).Intermediate F (0.04 g, 0.15 mmol) was added to the reaction mixture.The reaction mixture was stirred at ambient temperature for 3 h. LCMSdata shows product formation m/z 448. The reaction mixture was dilutedwith saturated solution of NaHCO₃ and extracted with Ethyl acetate. Theethyl acetate layer was separated and dried over anhydrous Na₂SO₄. Theevaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: EtOAc:Hexane (30:70 v/v mL).The desired product band was isolated to obtain 0.031 g of product(Yield 45.0%). MS (ESI) mass calcd. for C₂₈H₂₆N₆O, 447.5; m/z found447.9 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.59 (m, 2H)1.64-1.96 (m, 2H) 2.87-3.06 (m, 1H) 3.56-3.84 (m, 1H) 4.55 (br s, 3H)6.71 (s, 1H) 6.90-6.91 (m, 1H) 7.22-7.50 (m, 8H) 7.58-7.70 (m, 2H)7.71-7.90 (m, 3H) 8.53 (br d, J=6.68 Hz, 1H).

M. Example 13

Synthesis of Compound Example 13: Intermediate J (0.04 g, 0.16 mmol) wasdissolved in dry THF (2.5 mL). The HATU (0.064 g, 0.16 mmol) was addedfollowed by DIPEA (0.087 g, 0.67 mmol). Intermediate F (0.044 g, 0.16mmol) was added to the reaction mixture. The reaction mixture wasstirred at ambient temperature for 3 h. LCMS data shows productformation m/z 448. The reaction mixture was diluted with saturatedsolution of NaHCO₃ and extracted with Ethyl acetate. The ethyl acetatelayer was separated and dried over anhydrous Na₂SO₄. The evaporation ofsolvent gave crude product. The crude product was purified by prep-TLCplate, Mobile phase: EtOAc:Hexane (30:70 v/v mL). The desired productband was isolated to obtain 0.048 g of product (Yield 64.0%). MS (ESI)mass calcd. for C₂₅H₂₅N₅O, 447.5; m/z found 448.0 [M+H]⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.18-1.45 (m, 1H) 1.45-1.67 (m, 1H) 1.68-1.85 (m,1H) 1.90 (m, 1H) 2.86 (m, 1H) 3.06 (m, 1H) 4.35-4.58 (m, 2H) 4.63 (br s,1H) 6.75 (br s, 1H) 6.89-7.16 (m, 1H) 7.16-7.35 (m, 2H) 7.35-7.60 (m,6H) 7.71-7.87 (m, 5H) 8.79 (br d, J=6.68 Hz, 1H).

N. Example 14

Synthesis of Compound Example 14:2-Phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I)(0.029 g, 0.12 mmol) was dissolved in mixture of dry THF:DMF (2.0 mL,1:1). The HATU (0.046 g, 0.12 mmol) was added followed by DIPEA (0.062g, 0.5 mmol). Intermediate C (0.03 g, 0.12 mmol) was added to thereaction mixture. The reaction mixture was stirred at ambienttemperature for 3 h. LCMS data shows product formation m/z 427. Thereaction mixture was diluted with saturated solution of NaHCO₃ andextracted with Ethyl acetate. The ethyl acetate layer was separated anddried over anhydrous Na₂SO₄. The evaporation of solvent gave crudeproduct. The crude product was purified by prep-TLC plate, Mobile phase:EtOAc:Hexane (25:75 v/v mL). The desired product band was isolated toobtain 0.032 g of product (Yield 62.0%). MS (ESI) mass calcd. forC₂₅H₂₆N₆O, 426.5; m/z found 427.0 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δppm 1.01-1.38 (m, 3H) 1.52-1.93 (m, 4H) 2.20-2.43 (m, 2H) 2.55-2.89 (m,2H) 3.47-3.89 (m, 2H) 4.43-4.60 (m, 1H) 6.65-6.84 (m, 1H) 6.84-7.06 (m,1H) 7.08-7.29 (m, 1H) 7.29-7.47 (m, 4H) 7.47-7.54 (m, 2H) 7.55-7.76 (m,1H) 8.15 (s, 1H) 8.26 (br d, J=6.82 Hz, 1H).

O. Example 15

Synthesis of Compound Example 15: Intermediate J (0.024 g, 0.1 mmol) wasdissolved in dry THF (2.5 mL). The HATU (0.038 g, 0.1 mmol) was addedfollowed by DIPEA (0.052 g, 0.4 mmol). Intermediate C (0.024 g, 0.1mmol) was added to the reaction mixture. The reaction mixture wasstirred at ambient temperature for 16 h. LCMS data shows productformation m/z 427. The reaction mixture was diluted with saturatedsolution of NaHCO₃ and extracted with Ethyl acetate. The ethyl acetatelayer was separated and dried over anhydrous Na₂SO₄. The evaporation ofsolvent gave crude product. The crude product was purified by prep-TLCplate, Mobile phase: EtOAc:Hexane (75:25 v/v mL). The desired productband was isolated to obtain 0.034 g of product (Yield 76.0%). MS (ESI)mass calcd. for C₂₅H₂₆N₆O, 426.5; m/z found 426.9 [M+H]⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.14-1.29 (t, 3H) 1.40-1.95 (m, 4H) 2.21-2.45 (m,2H) 2.65-3.21 (m, 2H) 3.43-3.72 (m, 2H) 4.47 (br s, 1H) 6.67-6.95 (m,1H) 7.00 (br d, J=6.24 Hz, 1H) 7.12-7.29 (m, 1H) 7.30-7.45 (m, 4H)7.46-7.62 (m, 1H) 7.72 (br s, 2H) 8.14 (br s, 1H) 8.51-8.81 (br d, J=8.0Hz 1H).

P. Example 16

Synthesis of Compound Example 16: Intermediate A (0.025 g, 0.1 mmol) wasdissolved in dry DCM (2.0 mL). The EDC.HCl (0.039 g, 0.21 mmol) and HOBt(0.028 g, 0.21 mmol) were added followed by Et₃N (0.14 mL, 1.0 mmol).Intermediate G (0.03 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL) andadded to the reaction mixture. The reaction mixture was stirred atambient temperature for 16 h. LCMS data shows product formation m/z434.2. The reaction mixture was diluted with DCM and washed withsaturated solution of NaHCO₃. The DCM layer was separated and dried overanhydrous Na₂SO₄. The evaporation of solvent gave crude product. Thecrude product was purified by prep-TLC plate, Mobile phase: EtOAc:Hexane(60:40 v/v mL). The 31.3 mg of pure product was obtained (Yield 70.1%).MS (ESI) mass calcd. for C₂₄H₂₇N₅O₃, 433.5; m/z found 434.2 [M+H]⁺, ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.63 Hz, 3H) 1.48-1.75 (m,2H) 1.85-2.08 (m, 2H) 2.55 (q, J=7.58 Hz, 2H) 2.68-2.77 (m, 1H) 3.13(ddd, J=10.60, 6.97, 4.07 Hz, 1H) 3.49-3.99 (m, 1H) 4.00-4.27 (m, 4H)4.45-4.54 (m, 1H) 4.58-4.65 (br d, J=7.70 Hz, 1H) 4.82-5.01 (m, 2H)7.23-7.36 (m, 3H) 7.43-7.55 (m, 1H) 7.58 (br d, J=6.97 Hz, 1H) 8.18-8.29(m, 1H) 8.34 (s, 1H).

Q. Example 17

Synthesis of Compound Example 17: Intermediate A (0.025 g, 0.1 mmol) wasdissolved in dry DCM (3.0 mL). The EDC.HCl (0.039 g, 0.21 mmol) and HOBt(0.028 g, 0.21 mmol) were added followed by Et₃N (0.14 mL, 1.0 mmol).Intermediate H (0.033 g, 0.1 mmol) was added to the reaction mixture.The reaction mixture was stirred at ambient temperature for 16 h. LCMSdata shows product formation m/z 473.2. The reaction mixture was dilutedwith DCM and washed with saturated solution of NaHCO₃. The DCM layer wasseparated and dried over anhydrous Na₂SO₄. The evaporation of solventgave crude product. The crude product was purified by prep-TLC plate,Mobile phase: EtOAc:Hexane (40:60 v/v mL). The 0.045 g of product wasobtained (Yield 92.5%). MS (ESI) mass calcd. for C₂₄H₂₃F₃N₄O₃, 472.5;m/z found 473.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.61(m, 1H) 1.60-1.71 (m, 1H) 1.71-1.91 (m, 1H) 1.91-2.24 (m, 1H) 2.48-2.81(m, 1H) 3.01-3.26 (m, 1H) 3.45-3.93 (m, 1H) 3.95-4.23 (m, 4H) 4.39-4.71(m, 2H) 4.71-5.06 (m, 2H) 6.49-6.87 (m, 1H) 7.12-7.39 (m, 3H) 7.39-7.63(m, 2H) 7.63-7.84 (m, 1H) 8.19-8.54 (m, 1H).

R. Example 18

Synthesis of Compound Example 18:2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I)(0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). The EDC.HCl(0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added followed byEt₃N (0.15 mL, 1.1 mmol). Intermediate H (0.034 g, 0.11 mmol) was addedto the reaction mixture. The reaction mixture was stirred at ambienttemperature for 16 h. LCMS data shows product formation m/z 467. Thereaction mixture was diluted with DCM and washed with saturated solutionof NaHCO₃. The DCM layer was separated and dried over anhydrous Na₂SO₄.The evaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: EtOAc:Hexane (40:60 v/v mL).The 0.023 g of product was obtained (Yield 46.5%). MS (ESI) mass calcd.for C₂₅H₂₁F₃N₄O₂, 466.5; m/z found 467.2 [M+H]⁺, ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.24-1.52 (m, 1H) 1.52-1.74 (m, 1H) 1.76-2.11 (m,2H) 2.58-3.21 (br s, 1H) 3.64-3.92 (m, 1H) 3.92-4.18 (m, 1H) 4.49-4.72(m, 1H) 4.72-4.92 (m, 1H) 6.7-6.91 (br d, J=8.80 Hz, 2H) 7.17-7.30 (m,2H) 7.31-7.49 (m, 3H) 7.53-7.88 (m, 3H) 8.01-8.42 (br, 1H) 8.42-8.7 (br,1H).

S. Example 19

Synthesis of Compound Example 19:2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I)(0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). The EDC.HCl(0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added followed byEt₃N (0.15 mL, 1.1 mmol). Intermediate G (0.033 g, 0.11 mmol) was addedto the reaction mixture. The reaction mixture was stirred at ambienttemperature for 16 h. LCMS data shows product formation m/z 428. Thereaction mixture was diluted with DCM and washed with saturated solutionof NaHCO₃. The DCM layer was separated and dried over anhydrous Na₂SO₄.The evaporation of solvent gave crude product. The crude product waspurified by prep-TLC plate, Mobile phase: EtOAc:Hexane (75:25 v/v mL).The 0.017 g of product was obtained (Yield 37.4%). MS (ESI) mass calcd.for C₂₅H₂₅N₅O₂, 427.5; m/z found 428.2 [M+H]⁺, ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.18-1.39 (t, 3H) 1.47-1.67 (m, 1H) 1.67-1.85 (m,1H) 1.85-2.13 (m, 2H) 2.39-2.61 (m, 2H) 2.77-3.3 (br, 1H) 3.58-3.87 (m,1H) 3.88-4.15 (m, 1H) 4.59-4.6 (br d, J=7.41 Hz, 1H) 4.71-4.74 (br d,J=7.56 Hz, 1H) 6.83-6.86 (br t, J=6.64 Hz, 1H) 7.18-7.28 (m, 1H)7.33-7.42 (m, 3H) 7.54-7.70 (m, 1H) 7.78-7.80 (br d, J=7.26 Hz, 1H) 7.92(s, 1H) 8.33-8.40 (s, 1H) 8.41-8.65 (br d, J=6.31 Hz, 1H).

T. Example 20

Synthesis of Compound Example 20: Intermediate J (0.025 g, 0.11 mmol)was dissolved in dry DCM (2.0 mL). The EDC.HCl (0.04 g, 0.21 mmol) andHOBt (0.03 g, 0.21 mmol) were added followed by Et₃N (0.15 mL, 1.1mmol). Intermediate G (0.034 g, 0.11 mmol) was added to the reactionmixture. The reaction mixture was stirred at ambient temperature for 16h. LCMS data shows product formation m/z 467. The reaction mixture wasdiluted with DCM and washed with saturated solution of NaHCO₃. The DCMlayer was separated and dried over anhydrous Na₂SO₄. The evaporation ofsolvent gave crude product. The crude product was purified by prep-TLCplate, Mobile phase: EtOAc:Hexane (40:60 v/v mL). The 0.042 g of productwas obtained (Yield 84.9%). MS (ESI) mass calcd. for C₂₅H₂₁F₃N₄O₂,466.5; m/z found 467.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.51-1.69 (m, 1H) 1.70-1.82 (m, 1H) 1.82-2.02 (m, 1H) 2.03-2.16 (m, 1H)2.73-3.28 (m, 2H) 3.69-4.11 (m, 2H) 4.55-4.90 (m, 2H) 6.77-6.93 (m, 2H)7.13-7.26 (m, 1H) 7.32-7.53 (m, 3H) 7.56-7.92 (m, 4H) 8.05-8.59 (m, 2H).

U. Example 21

Synthesis of Compound Example 21: Intermediate J (0.025 g, 0.11 mmol)was dissolved in dry DCM (2.0 mL). The EDC.HCl (0.04 g, 0.21 mmol) andHOBt (0.03 g, 0.21 mmol) were added followed by Et₃N (0.15 mL, 1.1mmol). Intermediate G (0.033 g, 0.11 mmol) was added to the reactionmixture. The reaction mixture was stirred at ambient temperature for 16h. LCMS data shows product formation m/z 428. The reaction mixture wasdiluted with DCM and washed with saturated solution of NaHCO₃. The DCMlayer was separated and dried over anhydrous Na₂SO₄. The evaporation ofsolvent gave crude product. The crude product was purified by prep-TLCplate, Mobile phase: EtOAc:Hexane (60:40 v/v mL). The 0.029 g of productwas obtained (Yield 63.8%). MS (ESI) mass calcd. for C₂₅H₂₅N₅O₂, 427.5;m/z found 428.2 [M+H]⁺, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.1-1.23(t, 3H) 1.48-1.68 (m, 1H) 1.68-1.80 (m, 1H) 1.93-2.17 (m, 2H) 2.43-2.60(m, 2H) 2.82-3.22 (m, 1H) 3.75-4.0 (br, 2H) 4.53-4.75 (m, 2H) 6.76-6.85(m, 1H) 7.13-7.26 (m, 1H) 7.28-7.43 (m, 3H) 7.60-7.83 (m, 3H) 8.03 (s,1H) 8.31-8.39 (m, 2H) 8.43-8.45 (br d, J=6.90 Hz, 1H).

III. Experimental Biological Assays

Antagonistic activities on both orexin receptors have been measured foreach example compound using the following procedure:

In Vitro Assay: Intracellular Calcium Measurements:

Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptorand the human orexin-2 receptor, respectively, are grown in culturemedium (Ham F-12 with L-Glutamine) containing 300 μg/mL G418, 100 U/mLpenicillin, 100 μg/mL streptomycin and 10% heat inactivated fetal calfserum (FCS). The cells are seeded at 20′000 cells/well into 384-wellblack clear bottom sterile plates (Greiner). The seeded plates areincubated overnight at 37° C. in 5% CO2. Human orexin-A as an agonist isprepared as 1 mM stock solution in MeOH:water (1:1), diluted in HBSScontaining 0.1% bovine serum albumin (BSA), NaHCO₃: 0.375 g/L and 20 mMHEPES for use in the assay at a final concentration of 3 nM.

Antagonists are prepared as 10 mM stock solution in DMSO, then dilutedin 384-well plates using DMSO followed by a transfer of the dilutionsinto in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO₃: 0.375g/L and 20 mM HEPES. On the day of the assay, 50 μL of staining buffer(HBSS containing 1% FCS, 20 mM HEPES, NaHCO 3:0.375 g/L, 5 mM probenecid(Sigma) and 3 μM of the fluorescent calcium indicator fluo-4 AM (1 mMstock solution in DMSO, containing 10% pluronic) is added to each well.The 384-well cell-plates are incubated for 50 min at 37° C. in 5% CO₂followed by equilibration at RT for 30 min before measurement.

Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, MolecularDevices), antagonists are added to the plate in a volume of 10 μL/well,incubated for 120 min and finally 10 μL/well of agonist is added.Fluorescence is measured for each well at 1 second intervals, and theheight of each fluorescence peak is compared to the height of thefluorescence peak-induced by 3 nM orexin-A with vehicle in place ofantagonist. The IC50 value (the concentration of compound needed toinhibit 50% of the agonistic response) is determined and may benormalized using the obtained IC50 value of an on-plate referencecompound. Optimized conditions were achieved by adjustment of pipettingspeed and cell splitting regime. The calculated IC50 values mayfluctuate depending on the daily cellular assay performance.Fluctuations of this kind are known to those skilled in the art. In thecase where IC50 values have been determined several times for the samecompound, the geometric mean has been given. Antagonistic activities ofexample compounds are shown in Tables 1 and 2.

TABLE 1 Example of Compound data (% Inhibition at Orexin receptor type 1and type 2, @ 1 uM) % Inhibition of OX₁R @1 uM % Inhibition of OX₂R @1uM Example compound compound 1 69.72 28.21 2 62.84 20.90 3 14.01 14.24 485.70 12.80 5 70.97 0.4 6 87.57 38.45 7 80.10 2.44 8 86.10 13.75 9 76.81−2.51 10 86.92 43.54 11 67.13 21.62 12 88.90 46.14 13 96.60 78.53 1414.79 18.28 15 54.08 37.30 16 0.59 7.77 17 45.11 5.78 18 69.98 29.61 19−10.79 11.22 20 84.89 49.58 21 38.75 26.91

TABLE 2 Selected Compound IC₅₀ Example at Orexin receptor type 1 andtype 2 IC50 Kb IC50 Kb Example OX₁R (nM) OX₁R (nM) OX₂R (nM) OX₂R (nM) 133 7 2 122 26 4 3 0.8 5 136 29 6 8 1.7 7 9 2 8 5 1 9 59 12 10 3.5 0.7 1139 8 12 2 0.5 13 3 0.6 70 9 15 178 37 18 293 62 20 11 2

While certain embodiments have been described in terms of the preferredembodiments, it is understood that variations and modifications willoccur to those skilled in the art. Therefore, it is intended that theappended claims cover all such equivalent variations that come withinthe scope of the following claims.

What is claimed is:
 1. A compound of formula (I),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl; andwherein: A-B-J-D-E is a five-member heteroaryl; B-J-M-G-K-L is asix-member ring selected from the group consisting of aromatic, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl; and wherein, optionally: Ais N; and/or, B is C or N; and/or, J is C or N; and/or, D is C; and/or,E is C; and/or, M is selected from the group consisting of C, CH, CR₂R₃,CR₂, CR₃, O; and/or, G is selected from the group consisting of C, CH,CR₂R₃, CR₂, CR₃, and O; and/or, K is selected from the group consistingof C, CH, CR₂R₃, CR₂, CR₃, and O; and/or, L is selected from the groupconsisting of C, CH, CR₂R₃, CR₂, CR₃, and O.
 2. A compound of formulaII:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl; andwherein: M is selected from the group consisting of C, CH, CR₂R₃, CR₂,CR₃, O; and/or, G is selected from the group consisting of C, CH, CR₂R₃,CR₂, CR₃, and O; and/or, K is selected from the group consisting of C,CH, CR₂R₃, CR₂, CR₃, and O; and/or, L is selected from the groupconsisting of C, CH, CR₂R₃, CR₂, CR₃, and O.
 3. A compound of formulaIII:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl; andwherein: M is selected from the group consisting of C, CH, CR₂R₃, CR₂,CR₃, O; and/or, G is selected from the group consisting of C, CH, CR₂R₃,CR₂, CR₃, and O; and/or, K is selected from the group consisting of C,CH, CR₂R₃, CR₂, CR₃, and O; and/or, L is selected from the groupconsisting of C, CH, CR₂R₃, CR₂, CR₃, and O.
 4. A compound of formulaII-a:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 5. Acompound of formula II-b:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 6. Acompound of formula II-c:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 7. Acompound of formula III-a:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 8. Acompound of formula III-b:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 9. Acompound of formula III-c:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 10. Acompound of formula III-d:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄ alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; X is absent to provide apyrrolidine ring, CH₂ to provide a piperidine ring, or O to provide amorpholine ring; wherein the carbon atom at position 2 of the of thepiperidine ring or the pyrrolidine ring is optionally in absolute(S)-configuration; and wherein the carbon atom at position 2 of the ofthe morpholine ring is optionally in absolute (R)-configuration; Y isabsent or selected from the group consisting of NH, O, CH₂OR₄, CH₂, andNR₄R₇ wherein R₇ is H or alkyl; and, Z₁ and Z₂ are each independentlyselected from the group consisting of H, F, (C₁₋₄)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₂₋₇)cycloalkyl.
 11. Acompound of formula II-aa, II-ab, II-ac, II-ba, II-bb, II-bc, II-ca,II-cb, or II-cc:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; and, Y is absent or selected fromthe group consisting of NH, O, CH₂OR₄, CH₂, and NR₄R₇ wherein R₇ is H oralkyl.
 12. A compound of formula III-aa, III-ab, III-ac, III-ba, III-bb,III-bc, and III-ca, III-cb, or III-cc:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof; wherein: R₁ is selected from the groupconsisting of aromatic, aryl, five or six member heteroaryl, substitutedaromatic, substituted aryl, substituted five or six member heteroaryl;optionally wherein said heteroaryl is selected from the group consistingof pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; whereinsaid aromatic, aryl or heteroaryl is unsubstituted, mono-substituted byone R₁ substituent or di-substituted by two R₁ substituents, whereineach R₁ substituent is independently selected from the group consistingof (C₁₋₄)alkyl, (C₁₋₄ alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein the halogen isoptionally selected from the group consisting of F, Cl, Br, and I; R₂and R₃ are independently selected from the group consisting of H,halogen, alkyl, substituted alkyl, (C₁₋₄alkoxy, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein each R₂ and R₃ isindependently and optionally substituted at each substitutable positionwith up to three R₂-R₃ substituents, wherein each R₂-R₃ substituent isindependently selected from the group consisting of H, halogen, alkyl,substituted alkyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, and (C₃₋₇)cycloalkyl; wherein thehalogen is optionally selected from the group consisting of F, Cl, Br,and I; R₄ is selected from the group consisting of aromatic, aryl, fiveor six member heteroaryl; substituted aromatic, substituted aryl, andsubstituted five or six member heteroaryl; wherein said aromatic, arylor heteroaryl is unsubstituted, mono-substituted by one R₄ substituent,di-substituted by two R₄ substituents, or tri-substituted by three R₄substituents, wherein each R₄ substituent is independently selected fromthe group consisting of (C₁₋₄)alkyl, (C₁₋₄) alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, (C₃₋₇)cycloalkyl, and(C₃₋₇)heterocycloalkyl; and wherein the halogen is optionally selectedfrom the group consisting of F, Cl, Br, and I; R₅ is selected from thegroup consisting of CH₃, alkyl, and substituted alkyl; R₆ is selectedfrom the group consisting of H, halogen, alkyl, and substituted alkyl,wherein said halogen is selected from the group consisting of F, Cl, Br,and I; optionally wherein R₅ and R₆ connected as alkyl to form a(C₁₋₃)alkyl bridge cyclic structure; and, Y is absent or selected fromthe group consisting of NH, O, CH₂OR₄, CH₂, and NR₄R₇ wherein R₇ is H oralkyl.
 13. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof.
 14. A composition comprising a compound,pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer,or combination thereof according to any preceding claim.
 15. Apharmaceutical composition comprising a compound, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, isomer, or combinationthereof, of any one of claims 1-13; and at least one pharmaceuticallyacceptable excipient, carrier, adjuvant, or vehicle.
 16. Thepharmaceutical composition of claim 15 comprising a therapeuticallyeffective amount of the compound, pharmaceutically acceptable salt,hydrate, solvate, polymorph, isomer, or combination thereof.
 17. Thepharmaceutical composition according to claim 14, wherein saidcomposition further comprises at least one second therapeutic agent. 18.A method of preventing or treating a condition selected from the groupconsisting of a central nervous system (CNS) disorder, substanceaddiction, dependence, panic, anxiety, depression, posttraumatic stressdisorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimerdisease (AD) in a subject in need thereof, the method comprising thestep of administering to the subject a composition comprising acompound, pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof, of any one of claims 1-13.
 19. Themethod of claim 18 wherein the composition comprises a therapeuticallyeffective amount of the compound, pharmaceutically acceptable salt,hydrate, solvate, polymorph, isomer, or combination thereof.
 20. Themethod of claim 18 or 19 wherein the composition a pharmaceuticallyacceptable salt or isotope of the compound.
 21. The method of claim 18or 19 wherein the composition comprises an unlabeled form of thecompound or an isotopically labeled form of the compound in which thecompound has a structure depicted by the formula wherein one or moreatoms are replaced by an atom having a selected atomic mass or massnumber.
 22. Use of a compound, pharmaceutically acceptable salt,hydrate, solvate, polymorph, isomer, or combination thereof, of any oneof claims 1-13 in the preparation of a medicament for preventing and/ortreating a condition selected from the group consisting of a centralnervous system (CNS) disorder, substance addiction, dependence, panic,anxiety, depression, posttraumatic stress disorder (PTSD),neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD) ina subject in need thereof.
 23. The use of claim 22 wherein thecomposition comprises a therapeutically effective amount of thecompound, pharmaceutically acceptable salt, hydrate, solvate, polymorph,isomer, or combination thereof.
 24. The use of claim 22 or 23 whereinthe composition a pharmaceutically acceptable salt or isotope of thecompound.
 25. The use of any one of claims 22-24 wherein the compositioncomprises an unlabeled form of the compound or an isotopically labeledform of the compound in which the compound has a structure depicted bythe formula wherein one or more atoms are replaced by an atom having aselected atomic mass or mass number.
 26. A method for preparing acompound, the method comprising a reaction selected from the groupconsisting of: reacting Intermediate A with Intermediate F to produce acompound of Example 1; reacting Intermediate A with Intermediate B toproduce a compound of Example 2; reacting Intermediate A withIntermediate C to produce a compound of Example 3; reacting IntermediateJ with Intermediate D to produce a compound of Example 4; reactingIntermediate A with Intermediate D to produce a compound of Example 5;reacting Intermediate J with Intermediate E to produce a compound ofExample 6; reacting Intermediate A with Intermediate E to produce acompound of Example 7; reacting Intermediate I with Intermediate E toproduce a compound of Example 8; reacting Intermediate I withIntermediate D to produce a compound of Example 9; reacting IntermediateJ with Intermediate B to produce a compound of Example 10; reactingIntermediate I with Intermediate B to produce a compound of Example 11;reacting Intermediate I with Intermediate F to produce a compound ofExample 12; reacting Intermediate J with Intermediate F to produce acompound of Example 13; reacting Intermediate I with Intermediate C toproduce a compound of Example 14; reacting Intermediate J withIntermediate C to produce a compound of Example 15; reactingIntermediate A with Intermediate G to produce a compound of Example 16;reacting Intermediate A with Intermediate H to produce a compound ofExample 17; reacting Intermediate I with Intermediate H to produce acompound of Example 18; reacting Intermediate I with Intermediate G toproduce a compound of Example 19; reacting Intermediate J withIntermediate H to produce a compound of Example 20; and, reactingIntermediate J with Intermediate G to produce a compound of Example 21.